Benzenesulfonamide compounds and their use as therapeutic agents

ABSTRACT

This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy and/or epileptic seizure disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application No. 62/684,436, filed Jun. 13, 2018,which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to benzenesulfonamide compounds andpharmaceutical compositions comprising the compounds and methods ofusing the compounds and the pharmaceutical compositions in treatingsodium channel-mediated diseases or conditions, such as epilepsy and/orepileptic seizure disorder, as well as other diseases and conditionsassociated with the mediation of sodium channels.

BACKGROUND OF THE INVENTION

Voltage gated sodium channels (Na_(V)'s) are critical determinants ofcellular excitability in muscle and nerve (Hille, B, Ion Channels ofExcitable Membranes (2001), Sunderland, Mass., Sinauer Associates,Inc.). Four isoforms in particular, Na_(V)1.1, Na_(V)1.2, Na_(V)1.3, andNa_(V)1.6, account for the majority of sodium current in the neurons ofthe central nervous system. Na_(V)1.3 is primarily expressedembryonically. Beyond the neonatal stage, Na_(V)1.1, Na_(V)1.2, andNa_(V)1.6 are the critical isoforms that regulate neuronal signaling inthe brain (Catterall, W. A., Annual Review of Pharmacology andToxicology (2014), Vol. 54, pp. 317-338).

Na_(V)1.5 is expressed mainly in cardiac myocytes (Raymond, C. K. etal., J. Biol. Chem. (2004), Vol. 279, No. 44, pp. 46234-41), includingatria, ventricles, the sino-atrial node, atrio-ventricular node andcardiac Purkinje fibers. Mutations in human Na_(V)1.5 result in multiplearrhythmic syndromes, including, for example, long QT3 (LQT3), Brugadasyndrome (BS), an inherited cardiac conduction defect, sudden unexpectednocturnal death syndrome (SUNDS) and sudden infant death syndrome (SIDS)(Liu, H., et al., Am. J. Pharmacogenomics (2003), Vol. 3, No. 3, pp.173-9). Sodium channel blocker therapy has been used extensively intreating cardiac arrhythmias.

Epilepsy is a condition characterized by excessive synchronousexcitability in the brain that arises when the delicate balance ofexcitatory and inhibitory signals in the brain fall out of equilibrium.This can happen either due to an excess of excitation, or a deficiencyof inhibition. Mutations in the genes encoding Na_(V) channels have beenlinked to both types of disequilibrium.

Na_(V)1.1 has been identified as the primary Na_(V) isoform ofinhibitory interneurons (Yu, F. H. et al., Nat. Neurosci. (2006), Vol.9, pp. 1142-1149). These interneurons synapse on many other neurons,including excitatory glutamatergic neurons. Action potentials in theinterneurons induce the release of the neurotransmitter GABA onto otherneurons, hyperpolarizing them and thus dampening excitation. Thisresults in a negative feedback that enables controlled signaling andprevents local signals from expanding into waves of excitation thatspread across large brain regions. Because of this critical role ininhibitory interneurons, mutations that impair Na_(V)1.1 channelfunction can lead to a failure of those neurons to activate and releaseGABA (Ogiwara, I. et al., J. Neurosci. (2007), Vol. 27, pp. 5903-5914;Martin, M. S. et al., J. Biol. Chem. (2010), Vol. 285, pp. 9823-9834;Cheah, C. S. et al., Channels (Austin) (2013), Vol. 7, pp. 468-472; andDutton, S. B., et al., (2013), Vol. 49, pp. 211-220). The result is aloss in the inhibitory tone of the brain and a failure to contain theexcitability of the glutamatergic neurons. This failure of theinhibitory interneurons can result in aberrant wide-scale synchronousfiring of neurons across regions of the brain (epilepsy).

Mutations in the gene encoding Na_(V)1.1 (SCN1A) fall into two broadclasses, those that cause generalized epilepsy with febrile seizuresplus (GEFS+) and those that cause severe myoclonic epilepsy of infancy(SMEI), also known as Dravet Syndrome or early infantile epilepticencephalopathy 6 (EIEE6) (McKusik, V. K. et al., A EpilepticEncephalopathy, Early Infantile 6, EIEE6 (2012), Online MendelianInheritance in Man: John Hopkins University). SMEI mutations areheterozygous autosomal dominant mutations and are often caused by a genedeletion or truncation that leads to a channel with little or nofunction. The mutations arise de novo, or in a few cases have been shownto arise in asymptomatic mosaic parents (Tuncer, F. N. et al., EpilepsyResearch (2015), Vol. 113, pp. 5-10). Patients are born phenotypicallynormal and meet developmental milestones until the onset of seizures,typically between the age of 6 months and 1 year. This time of onset isbelieved to be a consequence of the normal decrease in the expression ofthe embryonic isoform Na_(V)1.3 and the coincident rise of Na_(V)1.1.When the Na_(V)1.1 channels fail to reach normal levels, the phenotypeis revealed (Cheah, C. S. et al., Channels (Austin) (2013), Vol. 7, pp.468-472). The initial seizure is often triggered by a febrile episodeand can manifest as status epilepticus. Seizures continue and increasein frequency and severity for the first several years of life and canreach frequencies of over 100 episodes per day. Seizures may betriggered by fever or may arise spontaneously without apparent cause.After seizure onset patients begin to miss developmental milestones andsignificant cognitive and behavioral deficits accrue (Dravet, C. andOguni, H., Handbook of Clinical Neurology (2013), Vol. 111, pp.627-633). 80 to 85% of phenotypically diagnosed Dravet syndrome patientsare believed to have a responsible mutation in SCN1A, while the other15-20% of patients have other mutations or are of unknown etiology.There is a high rate of sudden unexplained death in epilepsy (SUDEP) inSMEI patients, with an estimated 37% of patients dying by SUDEP, but themechanism for this catastrophic outcome remains unclear (Massey, C. A.,et al., Nature Reviews Neurology (2014), Vol. 10, pp. 271-282).Clinically useful anti-epileptic drugs that target voltage-gated sodiumchannels non-selectively, like carbamazepine and phenytoin, arecontra-indicated for SMEI patients as they can exacerbate seizures inthese patients (Wlmshurst, J. M. et al., Epilepsia (2015), Vol. 56, pp.1185-1197). This is presumed to be because patients cannot toleratefurther reductions in Na_(V)1.1 function.

GEFS+ is often caused by missense SCN1A mutations that induce relativelymild channel dysfunction, consistent with the relatively milder seizurephenotype. A large and growing number of mutations have been identified,and both the severity and the penetrance of the phenotype variesconsiderably. Many GEFS+ patients outgrow the seizure phenotype, howevernot all do, and GEFS+ patients with childhood epilepsy are considerablymore prone to have epilepsy as adults than are the general population.Mutations that cause deficits in other genes involved with GABA-ergicsignaling, like SCN1B that encodes the sodium channel auxiliary subunitand GABRG2 that encodes a subunit of GABA_(A) receptors can also giverise to GEFS+ (Helbig, I., Seminars in Neurology (2015) Vol. 35, pp.288-292).

Transgenic mice have been developed that harbor the same mutationsidentified in SMEI and GEFS+ patients. In both cases the mice replicatethe human phenotype well, though the penetrance of the phenotype can besignificantly impacted by the genetic background. Some mouse strainstolerate the mutations relatively well, while in other strains the samemutations can cause drastic seizure phenotypes. These differences arepresumed to be due to differing levels of expression of other genes thatmodulate the excitation phenotype (Miller, A. R. et al., Genes, Brain,and Behavior (2014), Vol. 13, pp. 163-172; Mistry, A. M. et al.,Neurobiology of Disease (2014), Vol. 65, pp. 1-11; and Hawkins, N. A. etal., Epilepsy Research (2016), Vol. 119, pp. 20-23).

In the brain, Na_(V)1.2 and Na_(V)1.6 are primarily expressed inexcitatory glutamatergic neurons. Both channels are especially dense inthe action initial segment (AIS), a region of the neuron adjacent to theneuronal soma that acts to integrate inputs and initiates actionpotential propagation to the soma and the distal dendrites (Royeck, M.et al., J. Neurophysiol. (2008), Vol. 100, pp. 2361-2380; Vega, A. V. etal., Neurosci. Lett. (2008), Vol. 442, pp. 69-73; and Hu, W. et al.,Nat. Neurosci. (2009), Vol. 12, pp. 996-1002). Na_(V)1.6 tends to beespecially densely localized the early AIS (distal from the soma) whereit is thought to act to trigger action potential initiation. Na_(V)1.2is more highly localized to the segment of the AIS most proximal to thesoma. Mutations in both SCN2A (Na_(V)1.2) and SCN8A (Na_(V)1.6) havebeen linked to epilepsy and cognitive delay. The effects of themutations are diverse both at the level of the impact on channelfunction, and on the patient phenotype. Both Na_(V)1.2 and Na_(V)1.6 arealso expressed in peripheral neurons. Na_(V)1.6 is especially dense atthe nodes of Ranvier of myelinated neurons, where it is critical formaintaining salutatory conduction and high speed neuronal signaling.

Only a handful of Na_(V)1.2 mutations have been described, but they areprimarily linked with central nervous system pathologies, especiallyepilepsy (Kearney, J. A. et al., Neuroscience (2001), Vol. 102, pp.307-317; Zerem, A. et al., European Journal of Paediatric Neurology:EJPN: Official Journal of the European Paediatric Neurology Society(2014), Vol. 18, pp. 567-571; Fukasawa, T. et al., Brain & Development(2015), Vol. 37, pp. 631-634; Howell, K. B. et al., Neurology (2015),Vol. 85, pp. 958-966; Saitoh, M. et al., Epilepsy Research (2015), Vol.117, pp. 1-6; Samanta, D. et al., Acta Neurologica Belgica (2015), Vol.115, pp. 773-776; Carroll, L. S. et al., Psychiatric Genetics (2016),Vol. 26, pp. 60-65; and Schwarz, N. et al., Journal of Neurology (2016),Vol. 263, pp. 334-343). The epilepsy mutations are presumed to beprimarily gain of function mutations, meaning that they lead to anincrease in the amount of sodium current and thereby increasingexcitability. Establishing the impact on channel function in vivo beyondreasonable doubt is challenging and some of these mutations may yet leadto loss of function phenotypes.

Mutations in SCN8A have likewise been reported to show a range of gainand loss of function effects on the Na_(V)1.6 channel though, forNa_(V)1.6, most mutations examined have been associated with gain offunction phenotypes. Mutations in Na_(V)1.6 have been linked withepilepsy and autism spectrum disorders (Trudeau, M. M. et al., Journalof Medical Genetics (2006), Vol. 43, pp. 527-530; Veeramah, K. R. etal., Am. J. Hum. Genet. (2012), Vol. 90, pp. 502-510; Vaher, U. et al.,Journal of Child Neurology (2013); de Kovel, C. G. et al., EpilepsyResearch (2014); Estacion, M. et al., Neurobiology of Disease (2014),Vol. 69, pp. 117-123; Ohba, C. et al., Epilepsia (2014), Vol. 55, pp.994-1000; Wagnon, J. L. et al., Human Molecular Genetics (2014); Kong,W. et al., Epilepsia (2015), Vol. 56, pp. 431-438; and Larsen, J. etal., Neurology (2015), Vol. 84, pp. 480-489). The best described SCN8Amutant patients have a syndrome known as early infantile epilepticencephalopathy, 13 (EIEE13). Over 100 EIEE13 patients have beenidentified. Patients typically present with intractable seizures betweenbirth and 18 months of age. Patients have developmental and cognitivedelay, and motor impairment often associated with chronic muscularhypotonia. The most severely impacted patients never gain sufficientmotor control to walk. Many are not verbal. Less severe phenotypes learnto walk and talk but are motor-impaired and miss cognitive and socialmilestones. Most of the identified mutations are missense mutations, andit is assumed that the specific functional impact of the mutationcontributes to the variability in the phenotype, though geneticbackground is also likely involved (Larsen, J. et al., Neurology (2015),Vol. 84, pp. 480-489). In contrast to SMEI patients, anecdotal evidencesuggests that anti-epileptic drugs that target voltage-gated sodiumchannels non-selectively can ameliorate symptoms in EIEE13 patients,though no controlled clinical trials have been completed (Boerma, R. S.et al., Neurotherapeutics: The Journal of the American Society forExperimental Neuro Therapeutics (2016), Vol. 13, pp. 192-197). Whilephenytoin does seem to provide efficacy for EIEE13 patients, it does soat a cost. Efficacy is only achieved at very high doses where thesignificant adverse effects are tolerated only because the patients arein such dire need. Adverse effects commonly associated with phenytointherapy include hepatic necrosis, hypertrichosis, nervousness, tremor ofhands, numbness, dizziness, drowsiness, tremor, depression, confusion,fatigue, constipation, vertigo, ataxia, mental status changes,myasthenia, mood changes, restlessness, irritability, and excitement. Itseems likely that a drug that selectively targets Na_(V)1.6 would retainefficacy while reducing its adverse event burden.

Loss of function mutations in SCN8A in mice lead to a phenotype known asmotor endplate disease (med) and multiple mutations and phenotypes werelinked to the med gene region prior to the identification of the SCN8Agene (Burgess, D. L. et al., Nat. Genet. (1995), Vol. 10, pp. 461-465).Mice with SCN8A^(med) mutations have varying degrees of musclehypotonia, consistent with the degree of dysfunction of the Na_(V)1.6function. Mice with the SCN8A^(med/jo) have Na_(V)1.6 channels that havea loss of function, but not null, phenotype. SCN8A^(med) andSCN8A^(med/jo) mice are resistant to seizures induced by chemical insult(flurothyl, kainic acid, and picrotoxin) (Martin, M. S. et al., HumanMolecular Genetics (2007), Vol. 16, pp. 2892-2899; Hawkins, N. A. etal., Neurobiology of Disease (2011), Vol. 41, pp. 655-660; and Makinson,C. D. et al., Neurobiology of Disease (2014), Vol. 68, pp. 16-25).Curiously, when SCN8A^(med/jo) mice are crossed with SCN1A^(null) mutantmice to produce a mouse that is heterozygous for both the SCN1A^(null)allele and the SCN8A^(med/jo) allele the double mutant mice have a muchimproved seizure and cognitive phenotype than those with only anSCN1A^(null) mutation (Martin, M. S. et al., Human Molecular Genetics(2007), Vol. 16, pp. 2892-2899). Such mice have a spontaneous seizureand death rate similar to wild type mice and their seizure thresholdafter chemical insult is also increased. A similar result occurs uponcrossing mice with missense mutations of SCN1A (a model for GEFS+) andmice with SCN8A loss of function mutations. Having a single allele ofSCN8A^(med/jo) protected the GEFS+ model mice from seizures andpremature death (Hawkins, N. A. et al., Neurobiology of Disease (2011),Vol. 41, pp. 655-660). The ability of SCN8A knock down to improveseizure resistance is not limited to knockouts where the gene isglobally absent throughout animal development. Knock down of SCN8A inadult mice either globally or specifically in the hippocampus via aCRE-LOX inducible knockout approach also improved resistance toelectrically and chemically induced seizures Makinson, C. D. et al.,Neurobiology of Disease (2014), Vol. 68, pp. 16-25). These data suggestthat the suppression of inhibitory signaling caused by decreasedNa_(V)1.1 current can be offset, at least in part, by suppressingexcitatory signaling via decreased in Na_(V)1.6 current.

Voltage-gated sodium channel antagonism is the most common mechanism ofwidely prescribed antiepileptic drugs (AED's) (Ochoa, J. R. et al.,Sodium Channel Blockers. In: Antiepileptic Drugs (2016), Vol. (Benbadis,S., ed) Medscape News & Perspectives). Carbamazepine, Eslicarbazepine,Oxcarbazepine, Lacosamide, Lamotrigine, Phenytoin, Rufinamide andZonisamide are all believed to act primarily by blocking that functionof Na_(V) channels. Despite the presumed mechanism of action, thesedrugs are relatively promiscuous. They block all Na_(V) channel isoformsindiscriminately, thus block of Na_(V)1.1 would be expected toproconvulsant. Block of Na_(V)1.6, and perhaps Na_(V)1.2, would beanticonvulsant. In addition to sodium channels, these compounds alsoblock other targets, including voltage-gated calcium channels. SelectiveNa_(V) antagonists that spare Na_(V)1.1 and other off-target receptorsare expected to have both improved efficacy and therapeutic indexrelative to the currently available Na_(V) blocking drugs.

There is therefore an unmet medical need to treat epilepsy and otherNa_(V)1.6 associated pathological states effectively and without adverseside effects due to the blocking of other sodium channels, such asNa_(V)1.1 and/or Na_(V)1.5. The present invention provides methods tomeet these critical needs.

SUMMARY OF THE INVENTION

The present invention is directed to benzenesulfonamide compounds andpharmaceutical compositions comprising the compounds and methods ofusing the compounds and the pharmaceutical compositions of the inventionfor the treatment of diseases or conditions associated with the activityof voltage-gated sodium channels, particularly, Na_(V)1.6 activity, suchas epilepsy and/or epileptic seizure disorder.

Accordingly, in one aspect, this invention is directed to compounds offormula (I):

wherein:

-   q is 1 or 2;-   r is 1 or 2;-   R¹ is hydrogen or alkyl;-   R² is thiazolyl, isothiazolyl or isoxazolyl;-   R^(3a) and R^(3b) are each independently hydrogen or alkyl;-   each R⁴ is independently halo or alkyl;-   R⁵ is halo;-   each R⁶ is independently halo or alkoxy;-   R⁷ is azabicyclo[2.2.1]heptanylalkyl or R⁷ is    ((methyl)(prop-2-yl)amino)alkyl when r is 2 and at least one R⁶ is    alkoxy;    as an individual stereoisomer, enantiomer or tautomer thereof or a    mixture thereof;    or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The compounds of the invention, which are compounds of formula (I) asdescribed above, as individual stereoisomers, enantiomers or tautomersthereof or mixtures thereof; or as pharmaceutically acceptable salts,solvates or prodrugs thereof, are useful in treating diseases orconditions associated with voltage-gated sodium channels, preferablyNa_(V)1.6. Preferably, the compounds of the invention are Na_(V)1.6inhibitors. More preferably, the compounds of the invention showselectivity of inhibiting Na_(V)1.6 as compared with inhibitingNa_(V)1.5 and/or Na_(V)1.1. Without wishing to be bound by theory, suchselectivity is thought to advantageously reduce any side effects whichmay be associated with the inhibition of Na_(V)1.5 and/or Na_(V)1.1.

In another aspect, the invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and a compound offormula (I), as described above, as a stereoisomer, enantiomer ortautomer thereof or mixtures thereof; or a pharmaceutically acceptablesalt, solvate or prodrug thereof.

In another aspect, the invention provides methods for the treatment ofepilepsy and/or epileptic seizure disorder in a mammal, preferably ahuman, wherein the methods comprise administering to the mammal in needthereof a therapeutically effective amount of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer or tautomerthereof or mixtures thereof; or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a method for treatingor lessening the severity of a disease, condition, or disorder in amammal where activation or hyperactivity of Na_(V)1.6 is implicated inthe disease, condition or disorder, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof; or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

In another aspect, the invention provides methods of treating orameliorating, but not preventing, epilepsy and/or epileptic seizuredisorder in a mammal, wherein the methods comprise administering to themammal in need thereof a therapeutically effective amount of a compoundof the invention, as set forth above, as a stereoisomer, enantiomer ortautomer thereof or mixtures thereof, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, or a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer or tautomerthereof or mixtures thereof, or a pharmaceutically acceptable salt,solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

In another aspect, the invention provides pharmaceutical therapy incombination with one or more other compounds of the invention or one ormore other accepted therapies or as any combination thereof to increasethe potency of an existing or future drug therapy or to decrease theadverse events associated with the accepted therapy. In one embodiment,the present invention relates to a pharmaceutical composition combiningcompounds of the present invention with established or future therapiesfor the indications listed herein.

In another aspect, this invention is directed to methods of selectivelyinhibiting a first voltage-gated sodium channel in a mammal over asecond voltage-gated sodium channel, wherein the method comprisesadministering to the mammal a inhibitory amount of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer or tautomerthereof or mixtures thereof; or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprising ainhibitory amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

In another aspect, this invention is directed to the use of thecompounds of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or the useof a pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, in thepreparation of a medicament for the treatment of a disease or conditionassociated with the activity of a voltage-gated sodium channel,preferably Na_(V)1.6, in a mammal and preferably wherein the disease orcondition is epilepsy and/or epileptic seizure disorder.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

In addition to the foregoing, as used in the specification and appendedclaims, unless specified to the contrary, the following terms have themeaning indicated:

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms, more preferably one to six carbon atoms, and whichis attached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.When specifically stated in the specification, an alkyl group may beoptionally substituted by one of the following groups: alkyl, alkenyl,halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl,heteroaryl, oxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂,—C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²², —N(R²⁰)C(O)R²²,—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2), —S(O)_(p)OR²² (where p is 1 to2), —S(O)_(t)R²² (where t is 0 to 2), and —S(O)_(p)N(R²⁰)₂ (where p is 1to 2) where each R²⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R²² is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to twelve carbon atoms,preferably two to eight carbon atoms and which is attached to the restof the molecule by a single bond, e.g., ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Whenspecifically stated in the specification, an alkenyl group may beoptionally substituted by one of the following groups: halo, cyano,nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²², —N(R²⁰)C(O)R²², —N(R²⁰)S(O)_(p)R²² (wherep is 1 to 2), —S(O)_(p)OR²² (where p is 1 to 2), —S(O)_(t)R²² (where tis 0 to 2), and —S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; and each R²² is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl group as defined above, e.g., methoxy, ethoxy, n-propoxy,isopropoxy and the like. When specifically stated in the specification,the alkyl group may be optionally substituted as defined above for analkyl radical. Preferably, “alkoxy” refers to methoxy or isopropoxy.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group orlinking two parts of the molecule, consisting solely of carbon andhydrogen, containing no unsaturation and having from one to twelvecarbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and thelike. The alkylene chain may optionally contain one or more heteroatomswherein a carbon in the alkylene chain is replaced with a heteroatomselected from oxygen, nitrogen or sulfur. The alkylene chain is attachedto the rest of the molecule through a single bond and to the radicalgroup through a single bond or is attached to two parts of the moleculethrough a single bond at each point of attachment. When specificallystated in the specification, an alkylene chain may be optionallysubstituted by one of the following groups: alkyl, alkenyl, halo,haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl,oxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²², —N(R²⁰)C(O)R²², —N(R²⁰)S(O)_(p)R²² (wherep is 1 to 2), —S(O)_(p)OR²² (where p is 1 to 2), —S(O)_(t)R²² (where tis 0 to 2), and —S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; and each R²² is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may included fused orbridged ring systems. Aryl radicals include, but are not limited to,aryl radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Whenspecifically stated in the specification, an aryl group may beoptionally substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkenyl, halo, haloalkyl,haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R²¹—OR²⁰,—R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—N(R²⁰)—R²³—OR²⁰, —R²¹—C(O)R²⁰,—R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²²,—R²¹—N(R²⁰)C(O)R²², —R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—R²¹—N═C(OR²⁰)R²⁰, —R²¹—S(O)_(p)OR²² (where p is 1 to 2),—R²¹—S(O)_(t)R²² (where t is 0 to 2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where pis 1 to 2) where each R²⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R²¹ isindependently a direct bond or a straight or branched alkylene chain;each R²² is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl,and each R²³ is a direct bond or a straight or branched alkylene chain.Preferably, the optional substituents on an optionally substituted arylgroup for R¹ herein are alkyl, optionally substituted cycloalkyl, halo,haloalkyl, cyano, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl—R²¹—OR²⁰ and —R²¹—N(R²⁰)₂, (where R²⁰ and R²¹ are as defined above).

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, and the like. When specifically stated in thespecification, a cycloalkyl group may be optionally substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰,—R²¹—N(R²⁰)—R²³—OR²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²)₂, —R²¹—N(R²⁰)C(O)OR²², —R²¹—N(R²⁰)C(O)R²²,—R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2), —R²¹—N═C(OR²⁰)R²⁰,—R²¹—S(O)_(p)OR²² (where p is 1 to 2), —R²¹—S(O)_(t)R²² (where t is 0 to2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; each R²¹ is independently a direct bond or a straightor branched alkylene chain; each R²² is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, and each R²³ is a direct bond or astraight or branched alkylene chain.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above. When specifically stated in the specification,the alkylene chain and/or the cycloalkyl radical may be optionallysubstituted as defined above for optionally substituted alkylene chainand optionally substituted cycloalkyl.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of two to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused, bridged and spiro ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, azetidinyl, 3-azabicyclo[3.1.0]hexan-3-yl,1-azaspiro[3.3]heptan-1-yl, 5-azaspiro[2.3]hexan-5-yl,azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl,1-oxa-6-azaspiro[3.4]octan-6-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl,6-oxa-1-azaspiro[3.3]heptan-1-yl, 6-azaspiro[3.4]octan-6-yl,7-oxa-2-azaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl,dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuryl,trioxanyl, trithianyl, thiazinanyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.When specifically stated in the specification, a heterocyclyl group maybe optionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R²¹—OR²⁰,—R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)—R²³—OR²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰,—R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²²,—R²¹—N(R²⁰)C(O)R²², —R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—R²¹—N═C(OR²⁰)R²⁰, —R²¹—S(O)_(p)OR²² (where p is 1 to 2),—R²¹—S(O)_(t)R²² (where t is 0 to 2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where pis 1 to 2) where each R²⁰ is independently hydrogen, alkyl, alkenyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R²¹ isindependently a direct bond or a straight or branched alkylene chain;each R²² is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, and each R²³ is a direct bond or a straight or branchedalkylene chain.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. When specifically stated in thespecification, the alkylene chain of the heterocyclylalkyl radical maybe optionally substituted as defined above for an optionally substitutedalkylene chain. When specifically stated in the specification, theheterocyclyl part of the heterocyclylalkyl radical may be optionallysubstituted as defined above for an optionally substituted heterocyclylgroup. Preferably the optional substituents on the optionallysubstituted heterocyclylalkyl group for R⁵ herein are halo.

“Azabicyclo[2.2.1]heptanylalkyl” refers to a radical of the formula—R_(b)R_(j) where R_(b) is an alkylene chain as defined above and R_(j)is azabicyclo[2.2.1]heptanyl. Preferably, R_(b) is a straight orbranched divalent hydrocarbon chain consisting solely of carbon andhydrogen, containing no unsaturation and having from one to eight carbonatoms, preferably a straight divalent hydrocarbon chain consisting ofone carbon or a branched divalent carbon consisting of two carbons.

“((Methyl)(prop-2-yl)amino)alkyl” refers to the radical of the formula—R_(b)N(R_(a))₂ where R_(b) is an alkylene chain as defined above andone R_(a) is methyl and the other R_(a) is prop-2-yl. Preferably, R_(b)is a straight or branched divalent hydrocarbon chain consisting solelyof carbon and hydrogen, containing no unsaturation and having from oneto eight carbon atoms, preferably one carbon atom.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pryrimidinonyl,pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl,quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl,thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl,tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). When specificallystated in the specification, a heteroaryl group may be optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo,thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R²¹—OR²⁰,—R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)—R²³—OR²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰,—R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²²,—R²¹—N(R²⁰)C(O)R²², —R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—R²¹—N═C(OR²⁰)R²⁰, —R²¹—S(O)_(p)OR²² (where p is 1 to 2),—R²¹—S(O)_(p)R²² (where t is 0 to 2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where pis 1 to 2) where each R²⁰ is independently hydrogen, alkyl, alkenyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R²¹ isindependently a direct bond or a straight or branched alkylene chain;each R²² is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, and each R²³ is a direct bond or a straight or branchedalkylene chain. Preferably, the optional substituents on an optionallysubstituted bicyclic heteroaryl group for R¹ herein are halo.Preferably, the optional substituents on an optionally substitutedmonocyclic heteroaryl group for R¹ herein are alkyl.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above. When specifically stated in the specification,the heteroaryl part of the heteroarylalkyl radical may be optionallysubstituted as defined above for an optionally substituted heteroarylgroup. When specifically stated in the specification, the alkylene chainpart of the heteroarylalkyl radical may be optionally substituted asdefined above for an optionally substituted alkylene chain.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi,T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. SymposiumSeries, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound of the invention in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amide derivatives of amine functional groupsin the compounds of the invention and the like.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of formula (I) beingisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabelledcompounds could be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction on the sodium channels, or binding affinity to pharmacologicallyimportant site of action on the sodium channels. Certainisotopically-labelled compounds of formula (I), for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. In oneembodiment of the invention, the compounds of formula (I) are enrichedwith deuterium. Such deuterated compounds can be achieved by methodsknown to one skilled in the art, such as exchanging protons withdeuterium or by synthesizing the molecule with enriched startingmaterials.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples and Preparations as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products are typically are identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets, (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution (“unsubstituted). When a functional group is described as“optionally substituted,” and in turn, substitutents on the functionalgroup are also “optionally substituted” and so on, for the purposes ofthis invention, such iterations are limited to five, preferably suchiterations are limited to two.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of a sodiumchannel-mediated disease or condition in the mammal, preferably a human.The amount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the condition and its severity, the manner of administration, and theage of the mammal to be treated, but can be determined routinely by oneof ordinary skill in the art having regard to his own knowledge and tothis disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(a) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(b) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(c) relieving (or ameliorating) the disease or condition, i.e., causingregression of the disease or condition; or

(d) relieving (or ameliorating) the symptoms resulting from the diseaseor condition, e.g., relieving epilepsy without addressing the underlyingdisease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallisation. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes enantiomers,which refers to two stereoisomers whose molecules are nonsuperimposablemirror images of one another. See, for example, Smith, M. B. and J.March, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 6th edition (Wiley, 2007), for a detailed description of thestructure and properties of enantiomers and stereoisomers.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

The use of parentheses and brackets in substituent groups is used hereinto conserve space. Accordingly, the use of parenthesis in a substituentgroup indicates that the group enclosed within the parentheses isattached directly to the atom preceding the parenthesis. The use ofbrackets in a substituent group indicates that the group enclosed withinthe brackets is also attached directly to the atom preceding theparenthesis.

“Enantiomers” refer to asymmetric molecules that can exist in twodifferent isomeric forms which have different configurations in space.Other terms used to designate or refer to enantiomers include“stereoisomers” (because of the different arrangement or stereochemistryaround the chiral center; although all enantiomers are stereoisomers,not all stereoisomers are enantiomers) or “optical isomers” (because ofthe optical activity of pure enantiomers, which is the ability ofdifferent pure enantiomers to rotate plane-polarized light in differentdirections).

The designations, “R” and “S”, for the absolute configuration of anenantiomer of the invention may appear as a prefix or as a suffix in thename of the compound; they may or may not be separated from theenantiomer name by a hyphen; they may or may not be hyphenated; and theymay or may not be surrounded by parentheses.

In the formulae depicted herein, a bond to a substituent and/or a bondthat links a molecular fragment to the remainder of a compound may beshown as intersecting one or more bonds in a ring structure. Thisindicates that the bond may be attached to any one of the atoms thatconstitutes the ring structure, so long as a hydrogen atom couldotherwise be present at that atom. Where no particular substituent(s) isidentified for a particular position in a structure, then hydrogen(s) ispresent at that position. For example, in the following structure (D),the bond attaching the R³⁰ substituent can be on any of the carbons,including the carbon to which the R³¹ is attached, provided that thevalency allows for such an attachment:

“Resolution” or “resolving” when used in reference to a racemic compoundor a racemic mixture of a compound of the invention refers to theseparation of the racemic compound or a racemic mixture into its twoenantiomeric forms (i.e., (+) and (−); (R) and (S) forms).

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using ChemDrawProfessional Version 18.0.0.231 software program, wherein the compoundsof the invention are named herein, for example, as derivatives of acentral core structure, e.g., the benzenesulfonamide structure. Forcomplex chemical names employed herein, a substituent group is namedbefore the group to which it attaches. For example, cyclopropylethylcomprises an ethyl backbone with cyclopropyl substituent. In chemicalstructure diagrams, all bonds are identified, except for some carbonatoms, which are assumed to be bonded to sufficient hydrogen atoms tocomplete the valency.

Accordingly, the compound of formula (I), as described above in theSummary of the Invention, wherein q and r are both 1, R¹ is hydrogen, R²is isothiazol-3-yl, R^(3a) and R^(3b) are each hydrogen, R⁴ is fluoro,R⁶ is fluoro and R⁷ is (7-azabicyclo[2.2.1]heptan-7-yl)methyl, i.e., thecompound of the following structure:

is named herein as4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide.

EMBODIMENTS OF THE INVENTION

One aspect of the invention are compounds of formula (I), as set forthabove in the Summary of the Invention, as an individual stereoisomer,enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate or prodrug thereof.

One embodiment of the invention are compounds of formula (I) wherein R⁷is azabicyclo[2.2.1]heptanylalkyl.

Of this embodiment, a further embodiment are compounds of formula (I)wherein R² is isothiazolyl.

Of this further embodiment, preferred embodiments are selected from:

-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide;    and-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide    2,2,2-trifluoroacetate.

Of the embodiment wherein R⁷ is azabicyclo[2.2.1]heptanylalkyl, anotherembodiment are compounds of formula (I) wherein R² is thiazolyl.

Of this embodiment, one further embodiment are compounds of formula (I)wherein r is 1.

Of this further embodiment, preferred embodiments are selected from:

-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide;-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide    2,2,2-trifluoroacetate;-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide    2,2,2-trifluoroacetate; and-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide    2,2,2-trifluoroacetate.

Of the further embodiment wherein R² is thiazolyl, another furtherembodiment are compounds of formula (I) where r is 2.

Of this further embodiment, preferred embodiments are selected from:

-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide    2,2,2-trifluoroacetate;-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide    2,2,2-trifluoroacetate;-   4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide    2,2,2-trifluoroacetate;-   (S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;    and-   (R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide.

Of the embodiment wherein R⁷ is azabicyclo[2.2.1]heptanylalkyl, anotherembodiment are compounds of formula (I) wherein R² is isoxazolyl.

Of this embodiment, preferred embodiments are compounds of formula (I)selected from:

-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide;    and-   4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide    2,2,2-trifluoroacetate.

Another embodiment of the invention are compounds of formula (I) whereinR⁷ is azabicyclo[2.2.1]heptanylalkyl.

Of this embodiment, a further embodiment are compounds of formula (I)where R⁷ is ((methyl)(prop-2-yl)amino)alkyl, provided that r is 2 and atleast one R⁶ is alkoxy.

Of this further embodiment, a further embodiment are compounds offormula (I) wherein R² is isothiazolyl.

Of the further embodiment where R⁷ is ((methyl)(prop-2-yl)amino)alkyl, ris 2 and at least one R⁶ is alkoxy, another further embodiment arecompounds of formula (I) wherein R² is thiazolyl.

Of this further embodiment, preferred compounds of formula (I) areselected from:

-   2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;-   2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;-   2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide    2,2,2-trifluoroacetate; and-   2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide    2,2,2-trifluoroacetate.

Of the further embodiment where R⁷ is ((methyl)(prop-2-yl)amino)alkyl, ris 2 and at least one R⁶ is alkoxy, another further embodiment arecompounds of formula (I) wherein R² is isoxazoyl.

Another embodiment of the invention are compounds of formula (I) whereinone R⁴ is in the ortho position relative to the —S(O)₂—N(H)—R²substituent.

Another embodiment of the invention are compounds of formula (I) whereinone R⁴ is in the ortho position relative to —C(R^(3a))(R^(3b))—.

Another embodiment of the invention are compounds of formula (I) whereinone R⁶ is in the ortho position relative to —C(R^(3a))(R^(3b))—.

Another embodiment of the invention are compounds of formula (I) whereinR⁵ is fluoro.

Another embodiment of the invention are compounds of formula (I) whereinone R⁴ is fluoro.

Another embodiment of the invention are compounds of formula (I) whereinone R⁴ is chloro.

Another embodiment of the invention are compounds of formula (I) whereinone R⁴ is methyl.

Another embodiment of the invention are compounds of formula (I) whereinone R⁴ is fluoro and another R⁴ is methyl.

Another embodiment of the invention are compounds of formula (I) whereinone R⁶ is fluoro.

Another embodiment of the invention are compounds of formula (I) whereinone R⁶ is fluoro and another R⁶ is methoxy.

Another embodiment of the invention are compounds of formula (I) whereinone R⁶ is fluoro and another R⁶ is isopropoxy.

Another embodiment of the invention are compounds of formula (I) whereinone R⁶ is fluoro and another R⁶ is fluoro.

Another embodiment of the invention is a method of using the compoundsof formula (I) as standards or controls in in vitro or in vivo assays indetermining the efficacy of test compounds in modulatingvoltage-dependent sodium channels.

Another embodiment of the invention are compounds of formula (Ia),compounds of formula (Ib), compounds of formula (Ic), compounds offormula (Id), compounds of formula (Id), compounds of formula (Ie),compounds of formula (If), compounds of formula (Ig), compounds offormula (Ih), compounds of formula (Ii), compounds of formula (Ij) orcompounds of formula (Ik), as individual stereoisomers, enantiomers ortautomers thereof or mixtures thereof; or pharmaceutically acceptablesalts, solvates or prodrugs thereof, as described below in thePreparation of the Compounds of the Invention.

Another embodiment of the invention is a method of preparing a compoundof formula (Ia), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 1.

Another embodiment of the invention is a method of preparing a compoundof formula (Ib), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 2.

Another embodiment of the invention is a method of preparing a compoundof formula (Ic), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 3.

Another embodiment of the invention is a method of preparing a compoundof formula (If), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 3.

Another embodiment of the invention is a method of preparing a compoundof formula (Ig), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 3.

Another embodiment of the invention is a method of preparing a compoundof formula (Id), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 4.

Another embodiment of the invention is a method of preparing a compoundof formula (Ie), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 5.

Another embodiment of the invention is a method of preparing a compoundof formula (Ia), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 6.

Another embodiment of the invention is a method of preparing a compoundof formula (Ih), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 7.

Another embodiment of the invention is a method of preparing a compoundof formula (Ii), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 8.

Another embodiment of the invention is a method of preparing a compoundof formula (Ij), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 9.

Another embodiment of the invention is a method of preparing a compoundof formula (Ik), as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable saltthereof, as described herein in Reaction Scheme 9.

It is understood that any embodiment of the compounds of the invention,as set forth above, and any specific substituent set forth herein for aparticular R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶ and R⁷ substituent in thecompounds of the invention, as set forth above, may be independentlycombined with other embodiments and/or substituents of compounds of theinvention to form embodiments of the inventions not specifically setforth above. In addition, in the event that a list of substituents isdisclosed for any particular R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ substituentin a particular embodiment and/or claim, it is understood that one ormore substituents may be deleted from the list and that the remaininglist of substituents will be considered to be an embodiment of theinvention.

Another aspect of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound of theinvention, as described above, as a stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable salt,solvate or prodrug thereof.

Another aspect of the invention is a method of treating a disease or acondition associated with Na_(V)1.6 activity in a mammal wherein thedisease or condition is epilepsy and/or epileptic seizure disorder andwherein the method comprises administering to the mammal in need thereofa therapeutically effective amount of a compound of the invention, asdescribed above, as a stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof.

In one embodiment of this aspect, the epilepsy or epileptic seizuredisorder is selected from photosensitive epilepsy, self-induced syncope,intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5disorder, childhood and juvenile absence epilepsy, Dravet syndrome,frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamichamartoma, infantile spasms/West's syndrome, juvenile myoclonicepilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS),epilepsy with myoclonic-absences, Ohtahara syndrome, Panayiotopoulossyndrome, PCDH19 epilepsy, progressive myoclonic epilepsies, Rasmussen'ssyndrome, ring chromosome 20 syndrome, reflex epilepsies, temporal lobeepilepsy, Lafora progressive myoclonus epilepsy, neurocutaneoussyndromes, tuberous sclerosis complex, early infantile epilepticencephalopathy, early onset epileptic encephalopathy, generalizedepilepsy with febrile seizures+, Rett syndrome, multiple sclerosis,Alzheimer's disease, autism, ataxia, hypotonia and paroxysmaldyskinesia.

In one embodiment of this embodiment, the epilepsy or epileptic seizuredisorder is selected from Dravet syndrome, infantile spasms/West'ssyndrome, temporal lobe epilepsy, Lennox-Gastaut syndrome (LGS),generalized epilepsy with febrile seizures+and early infantile epilepticencephalopathy.

Another aspect of the invention is a method of decreasing ion fluxthrough Na_(V)1.6 in a mammalian cell, wherein the method comprisescontacting the cell with a compound of the invention, as describedabove, as a stereoisomer, enantiomer or tautomer thereof or a mixturethereof; or a pharmaceutically acceptable salt, solvate or prodrugthereof.

Another aspect of the invention is a method of selectively inhibiting afirst voltage-gated sodium channel over a second voltage-gated sodiumchannel in a mammal, wherein the method comprises administering to themammal a modulating amount of a compound of the invention, as describedabove, as a stereoisomer, enantiomer or tautomer thereof or a mixturethereof; or a pharmaceutically acceptable salt, solvate or prodrugthereof.

In one embodiment of this aspect, the first voltage-gated sodium channelis Na_(V)1.6.

In another embodiment of this aspect, the first voltage-gated sodiumchannel is Na_(V)1.6 and the second voltage-gated sodium channel isNa_(V)1.5.

In another embodiment of this aspect, the first voltage-gated sodiumchannel is Na_(V)1.6 and the second voltage-gated sodium channel isNa_(V)1.1.

Specific embodiments of the compounds of the invention are described inmore detail below in the Preparation of the Compounds of the Inventionand in the Examples.

Utility and Testing of the Compounds of the Invention

The compounds of the invention modulate, preferably inhibit, ion fluxthrough a voltage-dependent sodium channel, preferably Na_(V)1.6, in amammal, especially in a human. Any such modulation, whether it bepartial or complete inhibition or prevention of ion flux, is sometimesreferred to herein as “blocking” and corresponding compounds as“blockers” or “inhibitors”. In general, the compounds of the inventionmodulate the activity of a voltage-gated sodium channel downwards byinhibiting the voltage-dependent activity of the sodium channel, and/orreduce or prevent sodium ion flux across a cell membrane by preventingsodium channel activity such as ion flux.

The compounds of the invention inhibit the ion flux through avoltage-dependent sodium channel, preferably Na_(V)1.6. The compounds ofthe invention are state or frequency dependent modifiers of the sodiumchannel, having a low affinity for the rested/closed state and a highaffinity for the inactivated state. These compounds are likely tointeract with overlapping sites located in the inner cavity of thesodium conducting pore of the channel similar to that described forother state-dependent sodium channel blockers (Cestèle, S., et al., op.cit.). These compounds may also be likely to interact with sites outsideof the inner cavity and have allosteric effects on sodium ion conductionthrough the channel pore.

Any of these consequences may ultimately be responsible for the overalltherapeutic benefit provided by these compounds.

Accordingly, the compounds of the invention are voltage-gated sodiumchannel inhibitors, preferably Na_(V)1.6 inhibitors, and are thereforeuseful for treating diseases and conditions, preferably epilepsy and/orepileptic seizure disorder, in mammals, preferably humans, and otherorganisms, including all those human diseases and conditions which arethe result of aberrant voltage-dependent sodium channel biologicalactivity, preferably aberrant Na_(V)1.6 activity, or which may beameliorated by modulation of voltage-dependent sodium channel biologicalactivity. In particular, the compounds of the invention, i.e., thecompounds of formula (I), as set forth above in the Summary of theInvention, as individual stereoisomers, enantiomers or tautomers thereofor mixtures thereof; or as pharmaceutically acceptable salts, solvatesor prodrugs thereof, are useful for treating diseases and conditions inmammals, preferably humans, which are the result of aberrantvoltage-dependent Na_(V)1.6 biological activity or which may beameliorated by the modulation, preferably the inhibition, of Na_(V)1.6biological activity. Preferably the compounds of the inventionselectively inhibit Na_(V)1.6 over Na_(V)1.5 and/or Na_(V)1.1.

As defined herein, a disease, disorder or condition associated withNa_(V)1.6 activity includes, but is not limited to, epilepsy and/orepileptic seizure disorder. Such epilepsy and/or epileptic seizuredisorders include, but are not limited to, photosensitive epilepsy,self-induced syncope, intractable epilepsy, Angelman syndrome, benignrolandic epilepsy, CDKL5 disorder, childhood and juvenile absenceepilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiencysyndrome, hypothalamic hamartoma, infantile spasms/West's syndrome,juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastautsyndrome (LGS), epilepsy with myoclonic-absences, Ohtahara syndrome,Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonicepilepsies, Rasmussen's syndrome, ring chromosome 20 syndrome, reflexepilepsies, temporal lobe epilepsy, Lafora progressive myoclonusepilepsy, neurocutaneous syndromes, tuberous sclerosis complex, earlyinfantile epileptic encephalopathy, early onset epilepticencephalopathy, generalized epilepsy with febrile seizures+, Rettsyndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia,hypotonia and paroxysmal dyskinesia.

The present invention therefore relates to compounds, pharmaceuticalcompositions and methods of using the compounds and pharmaceuticalcompositions for the treatment of diseases or conditions associated bythe activity of Na_(V)1.6 in a mammal, preferably a human, byadministering to the mammal, preferably the human, in need of suchtreatment an effective amount of a compound of the invention or anpharmaceutical composition comprising a compound of the invention.

The general value of the compounds of the invention in inhibiting theNa_(V)1.6 ion flux can be determined using the assays described below inthe Biological Assays section. Alternatively, the general value of thecompounds in treating conditions and diseases in humans may beestablished in industry standard animal models for demonstrating theefficacy of compounds in treating epilepsy and/or epileptic seizuredisorder. Animal models of human epileptic conditions have beendeveloped that result in reproducible sensory deficits over a sustainedperiod of time that can be evaluated by sensory testing.

For example, many rodent models have been developed to assess thepropensity for seizures or epileptiform activity (Klein, B. R. et al.,(2016), “Models Currently in Active Use. In: Epilepsy Therapy ScreeningProgram”, Vol. 2016, National Institute of Neurological Disorders andStroke). These include acute chemical or electrical insults that induceseizures, as well as chronic chemical or genetic insults that createseizure prone animals. These models can be used to determine therelative ability of a compound to promote or prevent seizure activity.The maximal electroshock seizure (MES) assay and the 6 hertz psychomotorseizure test (6 Hz) are two examples of acute insult seizure assays usedto evaluate anticonvulsive interventions (Suzuki, F. et al.,Neuroscience (1995), Vo. 64, pp. 665-674; Barton, M. E. et al., EpilepsyResearch (2001), Vol. 47, pp. 217-227). Both assays involve anelectrical insult applied with electrodes placed on the corneas or earsin order to provoke an acute seizure. Acute seizures may also be inducedchemically, for instance by administration of the proconvulsant ethercompound flurothyl (Makinson, C. D. et al., Exp. Neurol. (2016), Vol.275, Pt 1, pp. 46-58).

Genetic epilepsies have been linked to many distinct genes, includingmultiple voltage gated sodium channel genes. Genetically modified micecan be created that harbor mutations identified in human patients. Insome cases these genetic modifications result in animals that behavemuch like the human patients in whom the genetic variations wereinitially identified. Mutant mice can be used to test anticonvulsantinterventions. Such experiments can involve prevention of spontaneousseizures, or may make use of similar seizure provoking stimuli as thoseemployed in wild type mice. Animal models of early infantile epilepticencephalopathy 6 (EIEE6), also known as severe myoclonic epilepsy ofinfancy or Dravet syndrome, have been created by mutating the SCN1A genethat encodes the Na_(V)1.1 voltage gated sodium channel (Yu, F. H. etal., Nat. Neurosci. (2006), Vol. 9, pp. 1142-1149). Models of EIEE13have likewise been created by mutating the SCN6A gene that encodes theNa_(V)1.6 voltage gated sodium channel (Wagnon, J. L. et al., HumanMolecular Genetics (2014)). Both of these mouse strains provide theopportunity to evaluate potential therapeutic interventions that mightprove useful in clinical patient populations (Martin, M. S. et al., J.Biol. Chem. (2010), Vol. 285, pp. 9823-9834; and Martin, M. S. et al.,Human Molecular Genetics (2007), Vol. 16, pp. 2892-2899).

The present invention readily affords many different means foridentification of Na_(V)1.6 inhibitory agents that are useful astherapeutic agents. Identification of Na_(V)1.6 inhibitors can beassessed using a variety of in vitro and in vivo assays, e.g., measuringcurrent, measuring membrane potential, measuring ion flux, (e.g., sodiumor guanidinium), measuring sodium concentration, measuring secondmessengers and transcription levels, and using e.g., voltage-sensitivedyes, radioactive tracers, and patch-clamp electrophysiology.

One such protocol involves the screening of chemical agents for abilityto modulate the activity of a sodium channel thereby identifying it as amodulating agent.

A typical assay described in Bean et al., J. General Physiology (1983),83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004),141(1):47-54, uses patch-clamp techniques to study the behaviour ofchannels. Such techniques are known to those skilled in the art, and maybe developed, using current technologies, into low or medium throughputassays for evaluating compounds for their ability to modulate sodiumchannel behaviour.

Throughput of test compounds is an important consideration in the choiceof screening assay to be used. In some strategies, where hundreds ofthousands of compounds are to be tested, it is not desirable to use lowthroughput means. In other cases, however, low throughput issatisfactory to identify important differences between a limited numberof compounds. Often it will be necessary to combine assay types toidentify specific sodium channel modulating compounds.

Electrophysiological assays using patch clamp techniques is accepted asa gold standard for detailed characterization of sodium channel compoundinteractions, and as described in Bean et al., op. cit. and Leuwer, M.,et al., op. cit. There is a manual low-throughput screening (LTS) methodwhich can compare 2-10 compounds per day; a recently developed systemfor automated medium-throughput screening (MTS) at 20-50 patches (i.e.compounds) per day; and a technology from Molecular Devices Corporation(Sunnyvale, Calif.) which permits automated high-throughput screening(HTS) at 1000-3000 patches (i.e. compounds) per day.

One automated patch-clamp system utilizes planar electrode technology toaccelerate the rate of drug discovery. Planar electrodes are capable ofachieving high-resistance, cells-attached seals followed by stable,low-noise whole-cell recordings that are comparable to conventionalrecordings. A suitable instrument is the PatchXpress 7000A (AxonInstruments Inc, Union City, Calif.). A variety of cell lines andculture techniques, which include adherent cells as well as cellsgrowing spontaneously in suspension are ranked for seal success rate andstability. Immortalized cells (e.g. HEK and CHO) stably expressing highlevels of the relevant sodium ion channel can be adapted intohigh-density suspension cultures.

Other assays can be selected which allow the investigator to identifycompounds which block specific states of the channel, such as the openstate, closed state or the resting state, or which block transition fromopen to closed, closed to resting or resting to open. Those skilled inthe art are generally familiar with such assays.

Binding assays are also available. Designs include traditionalradioactive filter based binding assays or the confocal basedfluorescent system available from Evotec OAI group of companies(Hamburg, Germany), both of which are HTS.

Radioactive flux assays can also be used. In this assay, channels arestimulated to open with veratridine or aconitine and held in astabilized open state with a toxin, and channel blockers are identifiedby their ability to prevent ion influx. The assay can use radioactive²²[Na] and ¹⁴[C] guanidinium ions as tracers. FlashPlate & Cytostar-Tplates in living cells avoids separation steps and are suitable for HTS.Scintillation plate technology has also advanced this method to HTSsuitability. Because of the functional aspects of the assay, theinformation content is reasonably good.

Yet another format measures the redistribution of membrane potentialusing the FLIPR system membrane potential kit (HTS) available fromMolecular Dynamics (a division of Amersham Biosciences, Piscataway,N.J.). This method is limited to slow membrane potential changes. Someproblems may result from the fluorescent background of compounds. Testcompounds may also directly influence the fluidity of the cell membraneand lead to an increase in intracellular dye concentrations. Still,because of the functional aspects of the assay, the information contentis reasonably good.

Sodium dyes can be used to measure the rate or amount of sodium ioninflux through a channel. This type of assay provides a very highinformation content regarding potential channel blockers. The assay isfunctional and would measure Na+ influx directly. CoroNa Red, SBFIand/or sodium green (Molecular Probes, Inc. Eugene Oreg.) can be used tomeasure Na influx; all are Na responsive dyes. They can be used incombination with the FLIPR instrument. The use of these dyes in a screenhas not been previously described in the literature. Calcium dyes mayalso have potential in this format.

In another assay, FRET based voltage sensors are used to measure theability of a test compound to directly block Na influx. Commerciallyavailable HTS systems include the VIPR™ II FRET system (AuroraBiosciences Corporation, San Diego, Calif., a division of VertexPharmaceuticals, Inc.) which may be used in conjunction with FRET dyes,also available from Aurora Biosciences. This assay measures sub-secondresponses to voltage changes. There is no requirement for a modifier ofchannel function. The assay measures depolarization andhyperpolarizations, and provides ratiometric outputs for quantification.A somewhat less expensive MTS version of this assay employs theFLEXstation™ (Molecular Devices Corporation) in conjunction with FRETdyes from Aurora Biosciences. Other methods of testing the compoundsdisclosed herein are also readily known and available to those skilledin the art.

These results provide the basis for analysis of the structure-activityrelationship (SAR) between test compounds and the sodium channel.Certain substituents on the core structure of the test compound tend toprovide more potent inhibitory compounds. SAR analysis is one of thetools those skilled in the art may now employ to identify preferredembodiments of the compounds of the invention for use as therapeuticagents.

Modulating agents so identified are then tested in a variety of in vivomodels so as to determine if they are useful in treating the disease orcondition associated with the activity of the sodium channel ofinterest, preferably Na_(V)1.6, with minimal adverse events. The assaysdescribed below in the Biological Assays Section are useful in assessingthe biological activity of the instant compounds.

Typically, the efficacy of a compound of the invention is expressed byits IC₅₀ value (“Inhibitory Concentration—50%”), which is the measure ofthe amount of compound required to achieve 50% inhibition of theactivity of the target sodium channel over a specific time period.

In an alternative use of the invention, the compounds of the inventioncan be used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting Na_(V)1.6 activityin a biological sample or a mammal, preferably a human, which methodcomprises administering to the mammal, preferably a human, or contactingsaid biological sample with a compound of formula (I) or apharmaceutical composition comprising a compound of formula (I). Theterm “biological sample”, as used herein, includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Inhibition of Na_(V)1.6 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

The compounds of the invention, as set forth above in the Summary of theInvention, as stereoisomers, enantiomers, tautomers thereof or mixturesthereof, or pharmaceutically acceptable salts, solvates or prodrugsthereof, and/or the pharmaceutical compositions described herein whichcomprise a pharmaceutically acceptable excipient and one or morecompounds of the invention, as set forth above in the Summary of theInvention, as a stereoisomer, enantiomer or tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, can be used in the preparation of a medicament for thetreatment of diseases or conditions associated with voltage-gated sodiumchannel activity, preferably Na_(V)1.6 activity, in a mammal.

Pharmaceutical Compositions of the Invention and Administration

The present invention also relates to pharmaceutical compositioncontaining the compounds of the invention disclosed herein. In oneembodiment, the present invention relates to a composition comprisingcompounds of the invention in a pharmaceutically acceptable carrier,excipient or diluent and in an amount effective to modulate, preferablyinhibit, ion flux through a voltage-dependent sodium channel to treatsodium channel mediated diseases, such as epilepsy and/or epilepticseizure disorder, when administered to an animal, preferably a mammal,most preferably a human patient.

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. Theterm “parenteral” as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. Pharmaceutical compositions of the invention are formulatedso as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see The Science and Practice ofPharmacy, 20th Edition (Philadelphia College of Pharmacy and Science,2000). The composition to be administered will, in any event, contain atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, for treatment of a disease orcondition of interest in accordance with the teachings of thisinvention.

The pharmaceutical compositions useful herein also contain apharmaceutically acceptable carrier, including any suitable diluent orexcipient, which includes any pharmaceutical agent that does not itselfinduce the production of antibodies harmful to the individual receivingthe composition, and which may be administered without undue toxicity.Pharmaceutically acceptable carriers include, but are not limited to,liquids, such as water, saline, glycerol and ethanol, and the like. Athorough discussion of pharmaceutically acceptable carriers, diluents,and other excipients is presented in Remington's Pharmaceutical Sciences(Mack Pub. Co., N.J., current edition).

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 50% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10% by weight of the compound prior to dilution of theinvention.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is (for a 70 Kg mammal) from about0.001 mg/Kg (i.e., 0.07 mg) to about 100 mg/Kg (i.e., 7.0 g); preferablya therapeutically effective dose is (for a 70 Kg mammal) from about 0.01mg/Kg (i.e., 0.7 mg) to about 50 mg/Kg (i.e., 3.5 g); more preferably atherapeutically effective dose is (for a 70 Kg mammal) from about 1mg/kg (i.e., 70 mg) to about 25 mg/Kg (i.e., 1.75 g).

The ranges of effective doses provided herein are not intended to belimiting and represent preferred dose ranges. However, the mostpreferred dosage will be tailored to the individual subject, as isunderstood and determinable by one skilled in the relevant arts (see,e.g., Berkow et al., eds., The Merck Manual, 19^(th) edition, Merck andCo., Rahway, N.J., 2011; Brunton et al. eds., Goodman and Cilman's ThePharmacological Basis of Therapeutics, 12^(th) edition, McGraw-Hill2011; Avery's Drug Treatment: Principles and Practice of ClinicalPharmacology and Therapeutics, 3rd edition, ADIS Press, LTD., Williamsand Wilkins, Baltimore, Md. (1987), Ebadi, Pharmacology, Little, Brownand Co., Boston, (1985); Osolci al., eds., Remington's PharmaceuticalSciences, current edition, Mack Publishing Co., Easton, Pa.; Katzung,Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, Conn.(1992)).

The total dose required for each treatment can be administered bymultiple doses or in a single dose over the course of the day, ifdesired. Generally, treatment is initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. The diagnostic pharmaceutical compound orcomposition can be administered alone or in conjunction with otherdiagnostics and/or pharmaceuticals directed to the pathology, ordirected to other symptoms of the pathology. The recipients ofadministration of compounds and/or compositions of the invention can beany vertebrate animal, such as mammals. Among mammals, the preferredrecipients are mammals of the Orders Primate (including humans, apes andmonkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs),Rodenta (including mice, rats and hamsters), Lagamorpha (includingrabbits) and Carnivora (including cats, and dogs). Among birds, thepreferred recipients are turkeys, chickens and other members of the sameorder. The most preferred recipients are humans.

For topical applications, it is preferred to administer an effectiveamount of a pharmaceutical composition according to the invention totarget area, e.g., skin surfaces, mucous membranes, and the like, whichare adjacent to peripheral neurons which are to be treated. This amountwill generally range from about 0.0001 mg to about 1 g of a compound ofthe invention per application, depending upon the area to be treated,whether the use is diagnostic, prophylactic or therapeutic, the severityof the symptoms, and the nature of the topical vehicle employed. Apreferred topical preparation is an ointment, wherein about 0.001 toabout 50 mg of active ingredient is used per cc of ointment base. Thepharmaceutical composition can be formulated as transdermal compositionsor transdermal delivery devices (“patches”). Such compositions include,for example, a backing, active compound reservoir, a control membrane,liner and contact adhesive. Such transdermal patches may be used toprovide continuous pulsatile, or on demand delivery of the compounds ofthe present invention as desired.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems are well-known in the art andinclude osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations.

The compositions of the invention can also be delivered throughintra-nasal drug delivery systems for local, systemic, and nose-to-brainmedical therapies. Controlled Particle Dispersion (CPD)™ technology,traditional nasal spray bottles, inhalers or nebulizers are known bythose skilled in the art to provide effective local and systemicdelivery of drugs by targeting the olfactory region and paranasalsinuses.

The invention also relates to an intravaginal shell or core drugdelivery device suitable for administration to the human or animalfemale. The device may be comprised of the active pharmaceuticalingredient in a polymer matrix, surrounded by a sheath, and capable ofreleasing the compound in a substantially zero order pattern on a dailybasis similar to devices used to apply testosterone as described in PCTPublished Patent Application No. WO 98/50016.

Current methods for ocular delivery include topical administration (eyedrops), subconjunctival injections, periocular injections, intravitrealinjections, surgical implants and iontophoresis (uses a small electricalcurrent to transport ionized drugs into and through body tissues). Thoseskilled in the art would combine the best suited excipients with thecompound for safe and effective intra-ocular administration.

The most suitable route will depend on the nature and severity of thecondition being treated. Those skilled in the art are also familiar withdetermining administration methods (e.g., oral, intravenous, inhalation,sub-cutaneous, rectal etc.), dosage forms, suitable pharmaceuticalexcipients and other matters relevant to the delivery of the compoundsto a subject in need thereof.

Combination Therapy

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of diseases andconditions associated with voltage-gated sodium channel activity. Forexample, a compound of the invention may be administered simultaneously,sequentially or separately in combination with other therapeutic agents,including, but not limited to:

-   -   opiates analgesics, e.g., morphine, heroin, cocaine,        oxymorphine, levorphanol, levallorphan, oxycodone, codeine,        dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone,        hydromorphone, meripidine, methadone, nalorphine, naloxone,        naltrexone, buprenorphine, butorphanol, nalbuphine and        pentazocine;    -   non-opiate analgesics, e.g., acetaminophen, salicylates (e.g.,        aspirin);    -   nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., ibuprofen,        naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac,        diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,        flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,        meclofenamic acid, mefenamic acid, meloxicam, nabumetone,        naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin,        phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and        zomepirac;    -   anticonvulsants, e.g., carbamazepine, oxcarbazepine,        lamotrigine, valproate, topiramate, gabapentin and pregabalin;    -   antidepressants such as tricyclic antidepressants, e.g.,        amitriptyline, clomipramine, despramine, imipramine and        nortriptyline;    -   COX-2 selective inhibitors, e.g., celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib;    -   alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine,        guanfacine, dexmetatomidine, modafinil, and        4-amino-6,7-dimethoxy-2-(5-methane        sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)        quinazoline;    -   barbiturate sedatives, e.g., amobarbital, aprobarbital,        butabarbital, butabital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobartital, secobarbital,        talbutal, theamylal and thiopental;    -   tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1        antagonist, e.g., (αR,        9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione        (TAK-637),        5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine        (2S,3S);    -   coal-tar analgesics, in particular paracetamol;    -   serotonin reuptake inhibitors, e.g., paroxetine, sertraline,        norfluoxetine (fluoxetine desmethyl metabolite), metabolite        demethylsertraline, ′3 fluvoxamine, paroxetine, citalopram,        citalopram metabolite desmethylcitalopram, escitalopram,        d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin,        litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and        fluoxetine;    -   noradrenaline (norepinephrine) reuptake inhibitors, e.g.,        maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,        tomoxetine, mianserin, buproprion, buproprion metabolite        hydroxybuproprion, nomifensine and viloxazine (Vivalan®)),        especially a selective noradrenaline reuptake inhibitor such as        reboxetine, in particular (S,S)-reboxetine, and venlafaxine        duloxetine neuroleptics sedative/anxiolytics;    -   dual serotonin-noradrenaline reuptake inhibitors, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine, milnacipran and imipramine;    -   acetylcholinesterase inhibitors such as donepezil;    -   5-HT₃ antagonists such as ondansetron;    -   metabotropic glutamate receptor (mGluR) antagonists;    -   local anaesthetic such as mexiletine and lidocaine;    -   corticosteroid such as dexamethasone;    -   antiarrhythimics, e.g., mexiletine and phenytoin;    -   muscarinic antagonists, e.g., tolterodine, propiverine, tropsium        chloride, darifenacin, solifenacin, temiverine and ipratropium;    -   cannabinoids;    -   vanilloid receptor agonists (e.g., resinferatoxin) or        antagonists (e.g., capsazepine);    -   sedatives, e.g., glutethimide, meprobamate, methaqualone, and        dichloralphenazone;    -   anxiolytics such as benzodiazepines,    -   antidepressants such as mirtazapine,    -   topical agents (e.g., lidocaine, capsacin and resiniferotoxin);    -   muscle relaxants such as benzodiazepines, baclofen,        carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and        orphrenadine;    -   anti-histamines or H1 antagonists;    -   NMDA receptor antagonists;    -   5-HT receptor agonists/antagonists;    -   PDEV inhibitors;    -   Tramadol®;    -   cholinergic (nicotinic) analgesics;    -   alpha-2-delta ligands;    -   prostaglandin E2 subtype antagonists;    -   leukotriene B4 antagonists;    -   5-lipoxygenase inhibitors; and    -   5-HT₃ antagonists.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

Kits-of-Parts

The present invention also provides kits that contain a pharmaceuticalcomposition which includes one or more compounds of the invention. Thekit also includes instructions for the use of the pharmaceuticalcomposition for inhibiting the activity of voltage-gated sodiumchannels, preferably Na_(V)1.6, for the treatment of epilepsy, as wellas other utilities as disclosed herein. Preferably, a commercial packagewill contain one or more unit doses of the pharmaceutical composition.For example, such a unit dose may be an amount sufficient for thepreparation of an intravenous injection. It will be evident to those ofordinary skill in the art that compounds which are light and/or airsensitive may require special packaging and/or formulation. For example,packaging may be used which is opaque to light, and/or sealed fromcontact with ambient air, and/or formulated with suitable coatings orexcipients.

Preparation of the Compounds of the Invention

The following Reaction Schemes illustrate methods to make compounds offormula (I), as individual stereoisomers, enantiomers or tautomersthereof or mixtures thereof; or as pharmaceutically acceptable salts,solvates or prodrugs thereof, as described above in the Summary of theInvention.

It is understood that one skilled in the art would be able to make in asimilar manner as described below other compounds of the invention notspecifically illustrated below by using the appropriate startingcomponents and modifying the parameters of the synthesis as needed. Itis also understood that simple functional group transformations (see,e.g., Larock, R. C. Comprehensive Organic Transformations, 2^(nd)edition (Wiley, 1999) can be effected by methods known to one skilled inthe art. In general, starting components may be obtained from sourcessuch as Sigma Aldrich, Combi-Blocks, Oakwood Chemicals, Inc., Maybridge,Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesizedaccording to sources known to those skilled in the art (see, e.g.,Smith, M. B. and J. March, March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007)) orprepared as described herein.

It is also understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocess described below the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino include t-butoxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxymethyl and the like. Suitable protecting groups formercapto include —C(O)—R″ (where R″ is alkyl, aryl or aralkyl),p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acid include alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein.

The use of protecting groups is described in detail in Greene, T. W. andP. G. M. Wuts, Greene's Protective Groups in Organic Synthesis (currentedition), Wiley. The protecting group may also be a polymer resin suchas a Wang resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

The compounds of formula (I) may contain at least one asymmetric carbonatom and thus can exist as racemates, enantiomers and/ordiastereoisomers. Specific enantiomers or diastereoisomers may beprepared by utilizing the appropriate chiral starting material.Alternatively, diastereoisomeric mixtures or racemic mixtures ofcompounds of formula (I) may be resolved into their respectiveenantiomers or diastereoisomers. Methods for resolution ofdiastereoisomeric mixtures or racemic mixtures of the compounds offormula (I), as described herein, or intermediates prepared herein, arewell known in the art (e.g., E. L. Eliel and S. H. Wilen, inStereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994;Chapter 7, and references cited therein). Suitable processes such ascrystallization (e.g., preferential crystallization, preferentialcrystallization in the presence of additives), asymmetric transformationof racemates, chemical separation (e.g., formation and separation ofdiastereomers such as diastereomeric salt mixtures or the use of otherresolving agents; separation via complexes and inclusion compounds),kinetic resolution (e.g., with titanium tartrate catalyst), enzymaticresolution (e.g., lipase mediated) and chromatographic separation (e.g.,HPLC with chiral stationary phase and/or with simulated moving bedtechnology, or supercritical fluid chromatography and relatedtechniques) are some of the examples that may be applied (see e.g., T.J. Ward, Analytical Chemistry, 2002, 2863-2872).

Preparation of Compounds of Formula (I)

Compounds of formula (Ia) are compounds of formula (I) as describedabove in the Summary of the Invention wherein q is 1, R^(3a) and R^(3b)are each hydrogen, and R⁷ is azabicyclo[2.2.1]heptanylmethyl, and r, R¹,R², R⁵ and R⁶ are each as defined in the Summary of the Invention andcan be prepared by the method disclosed below in Reaction Scheme 1wherein n is 1 to 6, each X is independently fluoro, chloro or bromo,R^(4a) is bromo, R^(4b) is fluoro, R⁸ is alkyl and DPPA is diphenylphosphoryl azide:

Compounds of formula (A), (B), (D), (E), (G) and (H) are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds offormula (Ia) are prepared as described above in Reaction Scheme 1 asfollows:

A compound of formula (A) is first treated with azabicyclo[2.2.1]heptaneunder standard reaction conditions, such as, but not limited to, the useof a polar aprotic solvent, such as, but not limited to, dimethylsulfoxide, in the presence of a base, such as, but not limited to,potassium carbonate, at a temperature of between about 0° C. and 80° C.,for about 1 to 48 hours to afford a compound of formula (B).

The compound of formula (B) is then treated under standard catalytichydrogenation conditions, such as the use of Raney-Ni in the presence ofammonium hydroxide, to afford the compound of formula (C).

A compound of formula (D) is treated with an appropriate azide, such asdiphenyl phosphoryl azide and a compound of formula (E) under standardSchmidt rearrangement conditions to afford a compound of formula (F).

A compound of formula (G) is treated with an excess amount of compoundof formula (H) under standard arene sulfonylation conditions to afford acompound of formula (J). The compound of formula (F) is then treatedwith a compound of formula (J) under standard carbamate sulfonylationconditions to afford a compound of formula (K). The compound of formula(K) is then treated with a compound of formula (C) under standardnucleophilic aromatic substitution conditions, such as, but not limitedto, the use of a polar aprotic solvent, such as, but not limited to,dimethyl sulfoxide, in the presence of a base, such asN,N-diisopropylethylamine, at a temperature of between about 0° C. and80° C., for about 1 to 48 hours to afford a compound of formula (L).

The compound of formula (L) is then treated under standard areneprotodehalogenation conditions to afford a compound of formula (M),which is then treated under standard nitrogen deprotection conditions toafford a compound of formula (Ia).

Compounds of formula (Ib) are compounds of formula (I) as describedabove in the Summary of the Invention wherein q is 1, r is 2, R¹ ishydrogen, R^(3a) and R^(3b) are each hydrogen, R⁴ is halo, one R⁶ ishalo, one R⁶ is alkoxy (—OR⁸) and R⁷ is((methyl)(prop-2-yl)amino)methyl, and R² and R⁵ are each as defined inthe Summary of the Invention and can be prepared by the method disclosedbelow in Reaction Scheme 2 wherein each X is independently fluoro,chloro or bromo, R^(6a) is halo and R⁸ is alkyl:

Compounds of formula (F) are prepared in a similar manner as describedabove in Reaction Scheme 1. Compounds of formula (Ja) are prepared in asimilar manner as described above in Reaction Scheme 1 for compounds offormula (J). Compound of formula (N) is commercially available or can beprepared according to methods known to one skilled in the art or bymethods disclosed herein. In general, the compounds of formula (Ib) areprepared as described above in Reaction Scheme 2 as follows:

A compound of formula (Ja) is treated with a compound of formula (F) toafford a compound of formula (Ka) in a similar manner as described abovein Reaction Scheme 1 for the preparation of compound of formula (K) froma compound of formula (J) and a compound of formula (F).

A compound of formula (N) is treated under standard arene formylationconditions to form the aldehyde compound of formula (O), which is thentreated under standard nucleophilic aromatic substitution conditions toafford a compound of formula (P).

The compound of formula (P) is then treated under standard reductiveamination conditions to afford a compound of formula (Q).

The compound of formula (Q) is then treated under standard metal-halogenexchange/formylation/oxime formation conditions to afford a compound offormula (R).

The compound of formula (R) is then treated under standard oximereduction conditions to afford a compound of formula (S), which is thentreated with a compound of formula (Ka) under standard nucleophilicaromatic substitution reaction conditions, such as, but not limited to,the use of a polar aprotic solvent, such as, but not limited to,dimethyl sulfoxide, in the presence of a base, such asN,N-diisopropylethylamine, at a temperature of between about 0° C. and80° C., for about 1 to 48 hours to afford a compound of formula (T).

The compound of formula (T) is then treated under standardnitrogen-deprotection conditions to afford a compound of formula (Ib).

Alternatively, a compound of formula (P) where R⁸ is methyl is treatedunder standard demethylation conditions, such as, but not limited to,treatment with boron tribromide, to afford the corresponding hydroxycompound, which is then treated with an alkyl halide under standardWilliamson ether synthesis conditions to afford the corresponding alkoxycompound, which is then treated under the same conditions as describedabove from the preparation of a compound of formula (Q) to afford acompound of formula (Ib).

Compounds of formula (Ic), formula (If) and formula (Ig) are compoundsof formula (I), as described above in the Summary of the Inventionwherein q is 1, R^(3a) and R^(3b) are each hydrogen, and R⁷ isazabicyclo[2.2.1]heptanylmethyl, and r, R¹, R², R⁵ and R⁶ are each asdefined in the Summary of the Invention and can be prepared by themethod disclosed below in Reaction Scheme 3 wherein n is 1 to 6, each Xis independently fluoro, chloro or bromo, R^(4d) is alkyl, R^(4c) ischloro or fluoro and R⁸ is alkyl:

Compounds of formula (F), (Jb) and (C) can be prepared by methodsdisclosed herein. In general, the compounds of formula (Ia) are preparedas described above in Reaction Scheme 3 as follows:

A compound of formula (F) is treated with a compound of formula (Ja)under standard carbamate sulfonylation conditions to afford a compoundof formula (Kb). The compound of formula (Kb) is then treated with acompound of formula (C) under standard nucleophilic aromaticsubstitution conditions, such as, but not limited to, the use of a polaraprotic solvent, such as, but not limited to, dimethyl sulfoxide, in thepresence of a base, such as N,N-diisopropylethylamine, at a temperatureof between about 0° C. and 80° C., for about 1 to 48 hours to afford acompound of formula (La), which is then treated under standard nitrogendeprotection conditions to afford a compound of formula (Ic).

Alternatively, compounds of formula (La) are reacted with a boronic acidderivative, such as, but not limited to, R^(4d)—B(OH)₂, under standardSuzuki-Miyaura cross coupling conditions, such as, but not limited to,the use of a solvent such as, but not limited to, 1,4-dioxane, in thepresence of a base, such as, but not limited to, potassium phosphatetribasic, and in the presence of a palladium catalyst composed of, forexample, but not limited to, tetrakis(triphenylphosphine)palladium(0) orpalladium(II) acetate and tricyclohexylphosphine tetrafluoroborate, at atemperature of between about ambient temperature and 150° C., for about30 minutes to 16 hours to form a product, which is then deprotectedunder standard nitrogen deprotection conditions to afford a compound offormula (If).

Optionally, compounds of formula (La) are treated under standardnitrogen deprotection conditions to afford a compound of formula (Ig).

Compounds of formula (Id) are compounds of formula (I) as describedabove in the Summary of the Invention wherein q is 2, R^(3a) and R^(3b)are each hydrogen, R⁷ is azabicyclo[2.2.1]heptanylmethyl, and r, R¹, R²,R⁵ and R⁶ are each as defined in the Summary of the Invention and can beprepared by the method disclosed below in Reaction Scheme 3 wherein n is1 to 6, each X is fluoro, chloro or bromo, R^(4d) is alkyl, R^(4b) isfluoro and Pg¹ is a nitrogen-protecting group, such as 4-methoxybenzylor 2-(trimethylsilyl)ethoxy:

Compounds of formula (Jc) are prepared in a similar manner as describedabove in Reaction Scheme 1 for compounds of formula (J). Compounds offormula (C) are prepared in the manner described above in ReactionScheme 1 for compounds of formula (C). In general, compounds of formula(Id) are prepared as described above in Reaction Scheme 4 as follows:

A compound of formula R²—NH₂, which is commercially available or whichcan be prepared by methods known to one skilled in the art, is treatedwith a compound of formula (Jc) under standard sulfonamide formationconditions to afford a compound of formula (U).

The compound of formula (U) is the protected under standard nitrogenprotection conditions to afford a compound of formula (V).

The compound of formula (V) is then treated with a compound of formula(C) under standard nucleophilic aromatic substitution conditions, suchas, but not limited to, the use of a polar aprotic solvent, such as, butnot limited to, dimethyl sulfoxide, in the presence of a base, such asN,N-diisopropylethylamine, at a temperature of between about 0° C. and80° C., for about 1 to 48 hours to afford a compound of formula (W).

The compound of formula (W) is then reacted with a boronic acidderivative such as, but not limited to, R^(4d)—B(OH)₂, under standardSuzuki-Miyaura cross coupling conditions, such as, but not limited to,the use of a solvent, such as, but not limited to, 1,4-dioxane, in thepresence of a base, such as, but not limited to, potassium phosphatetribasic, and in the presence of a palladium catalyst composed of, forexample, but not limited to, tetrakis(triphenylphosphine)palladium(0) orpalladium(II) acetate and tricyclohexylphosphine tetrafluoroborate, at atemperature of between about ambient temperature and 150° C., for about30 minutes to 16 hours to generate a compound of formula (X), which isdeprotected under standard nitrogen deprotection conditions to afford acompound of formula (Id).

Compounds of formula (Ie) are compounds of formula (I) as describedabove in the Summary of the Invention wherein q is 1, R^(3a) and R^(3b)are each hydrogen, one R⁴ is alkyl and the other R⁴ is halo, R⁷ isazabicyclo[2.2.1]heptanylmethyl, and r, R¹, R², R⁵ and R⁶ are each asdefined in the Summary of the Invention and can be prepared by themethod disclosed below in Reaction Scheme 5 wherein n is 1 to 6, X isfluoro, chloro or bromo, R^(4a) is bromo, R^(4d) is alkyl, and R⁸ isalkyl:

Compounds of formula (F) are prepared as described above in ReactionScheme 1. Compounds of formula (Jb) are prepared in a similar manner asdescribed herein for compounds of formula (J). Compounds of formula (C)as described above in Reaction Scheme 1. In general, compounds offormula (Ie) are prepared as described above in Reaction Scheme 5 asfollows:

A compound of formula (F) is first treated under standard carbamatesulfonylation conditions to afford a compound of formula (Kc), which isthen treated with a compound of formula (C) under standard nucleophilicaromatic substitution conditions, such as, but not limited to, thepresence of a base, such, but not limited to, dimethyl sulfoxide, in thepresence of a base, such as N,N-diisopropylethylamine, at ambienttemperature for about 1 to 20 hours to afford a compound of formula(Lb). The compound of formula (Lb) is then reacted with a boronic acidderivative such as, but not limited to, R^(4d)—B(OH)₂, under standardSuzuki-Miyaura cross coupling conditions, such as, but not limited to,the use of a solvent, such as, but not limited to, 1,4-dioxane, in thepresence of a base, such as, but not limited to, potassium phosphatetribasic, and in the presence of a palladium catalyst composed of, forexample, but not limited to, tetrakis(triphenylphosphine)palladium(0) orpalladium(II) acetate and tricyclohexylphosphine tetrafluoroborate, at atemperature of between about ambient temperature and 150° C., for about30 minutes to 16 hours to generate a compound of formula (Lc), which isdeprotected under standard nitrogen deprotection conditions to afford acompound of formula (Ie).

Compounds of formula (Ia) as described above in Reaction Scheme 1 arealso prepared by the method disclosed below in Reaction Scheme 6 whereinq is 1, R^(3a) and R^(3b) are each hydrogen, and R⁷ isazabicyclo[2.2.1]heptanylmethyl, and r, R¹, R², R⁵ and R⁶ are each asdefined in the Summary of the Invention and wherein n is 1 to 6, X isfluoro, chloro or bromo, R^(4b) is fluoro and Pg¹ is anitrogen-protecting group, such as 4-methoxybenzyl or 2-(trimethylsilyl)ethoxy:

Compounds of formula (Va) can be prepared by the methods disclosedherein for compounds of formula (V) or by the methods disclosed in PCTPublished Patent Application No. WO 2018/106284. Compounds of formula(C) are prepared by the methods disclosed herein. In general, compoundsof formula (Ia) are prepared as described above in Reaction Scheme 6 asfollows:

A compound of formula (Va) is first treated with a compound of formula(C) under standard nucleophilic aromatic substitution conditions, suchas, but not limited to, the use of a polar aprotic solvent, such as, butnot limited to, dimethyl sulfoxide, in the presence of a base, such aspotassium carbonate, to afford a compound of formula (Wa), which is thendeprotected under standard nitrogen deprotection conditions to afford acompound of formula (Ia).

Compounds of formula (Ih) are compounds of formula (I) as describedabove in the Summary of the Invention wherein q is 1, R^(3a) and R^(3b)are each hydrogen, and R⁷ is azabicyclo[2.2.1]heptanylmethyl and r, R¹,R², R⁵ and R⁶ are each as defined in the Summary of the Invention andare prepared as described below in Reaction Scheme 7 wherein m is 0 to5, each X is independently fluoro, chloro or bromo, R^(4b) is fluoro andR⁹ is hydrogen or methyl, and Pg¹ is a nitrogen-protecting group, suchas 4-methoxybenzyl or 2-(tri methylsilyl)ethoxy:

Compounds of formula (Y) are commercially available or can be preparedby methods known to one skilled in the art. Compounds of formulae (C)and (Va) are prepared by methods described herein or by methods known toone skilled in the art. In general, compounds of formula (Ih) areprepared as described above in Reaction Scheme 7 as follows:

A compound of formula (Y) is first treated with a brominating agentunder standard Appel reaction conditions to afford a compound of formula(Z), which is then treated with azabicyclo[2.2.1]heptane under standardreaction conditions, such as, but not limited to, the use of a polaraprotic solvent, such as, but not limited to, dimethyl sulfoxide, in thepresence of a base, such as, but not limited to, potassium carbonate, ata temperature of between about 0° C. and 80° C., for about 1 to 48 hoursto afford a compound of formula (AA). The compound of formula (AA) isthen treated under standard metal-halogen exchange/formylation/oximeformation conditions to afford a compound of formula (BB), which is thentreated under standard oxime reduction conditions to afford a compoundof formula (Ca). The compound of formula (Ca) is then treated with acompound of formula (Va) under standard nucleophilic aromaticsubstitution conditions, such as, but not limited to, the use of a polaraprotic solvent, such as, but not limited to, dimethyl sulfoxide, in thepresence of a base, such as N,N-diisopropylethylamine, at a temperatureof between about 0° C. and 80° C., for about 1 to 48 hours to afford acompound of formula (Wa), which is then treated under standard nitrogendeprotection conditions to afford a compound of formula (Ih).

Compounds of formula (Ih) where R⁸ is methyl are further treated understandard chiral resolution conditions, preferably by preparativesupercritical fluid chromatography, to afford the individualenantiomers.

Compounds of formula (Ii) are compounds of formula (I) as describedabove in the Summary of the Invention wherein q is 1, r is 2, R^(3a) andR^(3b) are each hydrogen, and R⁷ is ((methyl)(prop-2-yl)amino)methyl,and R¹, R², and R⁵ are each as defined in the Summary of the Invention,and are prepared as described below in Reaction Scheme 8 wherein X isindependently fluoro, chloro or bromo, R^(4c) is chloro or bromo, R^(6a)is halo and R⁸ is alkyl:

Compounds of formulae (S) and (Kb) are prepared as disclosed herein. Ingeneral, compounds of formula (Ii) are prepared as described above inReaction Scheme 8 as follows:

A compound of formula (S) is first treated with a compound of formula(Kb) under standard nucleophilic aromatic substitution reactionconditions, such as, but not limited to, the use of a polar aproticsolvent, such as, but not limited to, dimethyl sulfoxide, in thepresence of a base, such as N,N-diisopropylethylamine, at a temperatureof between about 0° C. and 80° C., for about 1 to 48 hours to afford acompound of formula (CC), which is then treated under standardnitrogen-deprotection conditions to afford a compound of formula (Ii).

Compounds of formula (Ij) and formula (Ik) are compounds of formula (I)as described above in the Summary of the Invention wherein q is 1, r is2, R^(3a) and R^(3b) are each hydrogen, and R⁷ is((methyl)(prop-2-yl)amino)methyl, and R¹, R², and R⁵ are each as definedin the Summary of the Invention, and are prepared as described below inReaction Scheme 8 wherein X is independently fluoro, chloro or bromo,R^(4c) is chloro or bromo, R^(4d) is alkyl, R^(6a) is halo and R⁸ isalkyl:

Compounds of formulae (S) and (Kd) are prepared by methods similar tothose described herein. In general, compounds of formula (Ij) areprepared as described above in Reaction Scheme 9 as follows:

A compound of formula (S) is first treated with a compound of formula(Kd) under standard nucleophilic aromatic substitution reactionconditions, such as, but not limited to, the use of a polar aproticsolvent, such as, but not limited to, dimethyl sulfoxide, in thepresence of a base, such as N,N-diisopropylethylamine, at a temperatureof between about 0° C. and 80° C., for about 1 to 48 hours to afford acompound of formula (DD), which is then treated under standardnitrogen-deprotection conditions to afford a compound of formula (Ij).

Alternatively, a compound of formula (DD) is reacted with a boronic acidderivative, such as, but not limited to, R^(4d)—B(OH)₂, under standardSuzuki-Miyaura cross coupling conditions, such as, but not limited to,the use of a solvent such as, but not limited to, 1,4-dioxane, in thepresence of a base, such as, but not limited to, potassium phosphatetribasic, and in the presence of a palladium catalyst composed of, forexample, but not limited to, tetrakis(triphenylphosphine)palladium(0) orpalladium(II) acetate and tricyclohexylphosphine tetrafluoroborate, at atemperature of between about ambient temperature and 150° C., for about30 minutes to 16 hours to afford a compound of formula (EE), which isthen deprotected under standard nitrogen deprotection conditions toafford a compound of formula (Ik).

All of the compounds described below as being prepared which may existin free base or acid form may be converted to their pharmaceuticallyacceptable salts by treatment with the appropriate inorganic or organicbase or acid. Salts of the compounds prepared below may be converted totheir free base or acid form by standard techniques. Furthermore, allcompounds of the invention which contain an acid or an ester group canbe converted to the corresponding ester or acid, respectively, bymethods known to one skilled in the art or by methods described herein.

The following Examples, which are directed to the synthesis of thecompounds of the invention, and the following Biological Examples areprovided as a guide to assist in the practice of the invention, and arenot intended as a limitation on the scope of the invention.

In the Examples below, unless otherwise indicated all temperatures areset forth in degrees Celsius. Commercially available reagents werepurchased from suppliers such as Aldrich Chemical Company, Combi-Blocks,TCI or Oakwood Chemicals and were used without further purificationunless otherwise indicated. The reactions set forth below were donegenerally under a positive pressure of nitrogen or argon or with adrying tube (unless otherwise stated) in anhydrous solvents, and thereaction flasks were typically fitted with rubber septa for theintroduction of substrates and reagents via syringe. Glassware was ovendried and/or heat dried. Yields were not optimized. Melting points weredetermined on a Büchi hot-stage apparatus and are uncorrected. ¹H NMR,¹⁹F and ¹³C NMR data were obtained in deuterated CDCl₃, DMSO-d₆, CD₃OD,CD₃CN, or acetone-d₆ solvent solutions with chemical shifts (δ) reportedin parts-per-million (ppm) relative to trimethylsilane (TMS) or theresidual non-deuterated solvent peaks as the reference standard. Dataare reported as follows, if applicable: chemical shift, multiplicity,coupling constant in Hz, and number of protons, fluorine or carbonatoms. When peak multiplicities are reported, the following abbreviatesare used: s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet, br (broadened), dd (doublet of doublets), dt (doublet oftriplets). Coupling constants, when given, are reported in Hz (Hertz).

Example 1 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide

Step 1. Preparation of2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzonitrile

To a solution of 2-(bromomethyl)-6-fluorobenzonitrile (6.95 g, 32.5mmol) and 7-azabicyclo[2.2.1]heptane hydrochloride (4.35 g, 32.5 mmol)in anhydrous dimethyl sulfoxide (60 mL) was added potassium carbonate(9.0 g, 65.2 mmol). The resulting suspension was stirred at ambienttemperature for 12 h. The mixture was then diluted with ethyl acetate(400 mL) and water (100 mL). The aqueous layer was separated andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (3×100 mL), dried over anhydrous sodium sulfate,filtered and the filtrate concentrated in vacuo. The residue waspurified by column chromatography, eluting with a gradient of 0 to 5%methanol in dichloromethane, to yield the title compound as a yellow oil(6.40 g, 86% yield): MS (ES+) m/z 231.2 (M+1).

Step 2. Preparation of(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine

To a suspension of2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzonitrile (6.40 g,189 mmol) and Raney-Ni (3 mL of a ˜50% w/w aqueous slurry) in methanol(210 mL) was added 30% aqueous ammonium hydroxide (7.5 mL). Thesuspension was degassed under vacuum and purged with hydrogen severaltimes. The reaction mixture was then stirred under hydrogen atmosphere(1 atm) at ambient temperature for 12 h. The reaction mixture wasfiltered through celite and the filtrate was concentrated in vacuo. Theresidue was dissolved in dichloromethane (250 mL) and the solution wasdried over anhydrous sodium sulfate. Filtration and concentration of thefiltrate in vacuo provided a residue which was further dried byazeotropic distillation with toluene (2×50 mL), to afford the titlecompound as a brown syrup (6.70 g, quantitative yield) which was usedwithout further purification: ¹H NMR (300 MHz, CDCl₃) δ 7.09 (q, J=7.2Hz, 1H), 6.95 (t, J=8.6 Hz, 2H), 3.87 (s, 2H), 3.53 (s, 2H), 3.17 (t,J=2.0 Hz, 2H), 2.09 (s, 2H), 1.72 (dd, J=0.7, 0.4 Hz, 4H), 1.28-1.25 (m,4H); MS (ES+) m/z 235.2 (M+1).

Step 3. Preparation of Tert-Butyl Isothiazol-4-Ylcarbamate

To a stirred suspension of isothiazole-3-carboxylic acid (10.02 g, 77.6mmol) in anhydrous tert-butanol (80 mL) and anhydrous toluene (120 mL)was slowly added triethylamine (13.0 mL, 93.12 mmol). The mixture wasstirred at ambient temperature for 5 minutes and then diphenylphosphoryl azide (18.42 mL, 85.36 mmol) was added dropwise to it. Thereaction mixture was stirred at ambient temperature for 1 h, graduallywarmed to 85° C. over 1 h, and then heated at 85° C. with stirring for 7h. After cooling to ambient temperature, the reaction mixture wasdiluted with ethyl acetate (150 mL) and saturated aqueous sodiumbicarbonate (150 mL). The layers were separated and the aqueous layerwas extracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (150 mL), brine (150 mL), dried over magnesiumsulfate, and filtered. Concentration of the filtrate in vacuo provided aresidue, which was purified by column chromatography, eluting with agradient of 0 to 10% of ethyl acetate in heptane. Further purificationby column chromatography, eluting with a gradient of 0 to 10% of ethylacetate in dichloromethane, afforded the title compound as a colorlesssolid (10.33 g, 66% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.56 (dd, J=4.9,0.6 Hz, 1H), 8.11 (s, 1H), 7.66 (d, J=4.9 Hz, 1H), 1.53 (s, 9H); MS(ES+) m/z 201.1 (M+1).

Step 4. Preparation of 3-bromo-2,4,6-trifluorobenzenesulfonyl Chloride

To 2-bromo-1,3,5-trifluorobenzene (50.0 g, 236.0 mmol) was addedchlorosulfonic acid (250 mL) and the reaction mixture was heated to 80°C. for 12 h.

After cooling to ambient temperature, the reaction mixture was pouredonto ice-water and extracted with ethyl acetate (2×500 mL). The combinedorganic phase was dried over anhydrous sodium sulfate, filtered and thefiltrate concentrated in vacuo. Purification of the residue by columnchromatography, eluting with petroleum ether, provided the titlecompound as a yellow oil, which solidified upon standing (51.0 g, 70%yield): ¹H NMR (400 MHz, CDCl₃) δ 7.03 (ddd, J=9.8, 7.8, 2.2 Hz, 1H).

Step 5. Preparation of tert-butyl((3-bromo-2,4,6-trifluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate

To a solution of tert-butyl isothiazol-3-ylcarbamate (6.03 g, 30.11mmol) in anhydrous tetrahydrofuran (150 mL) was added a 1 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (33 mL, 33.0 mmol)at −78° C. The reaction mixture was stirred for 10 minutes at −78° C.,and then allowed to warm to ambient temperature and stirred for 1 h.After cooling the reaction mixture to −78° C., a cold (−78° C.) solutionof 3-bromo-2,4,6-trifluorobenzenesulfonyl chloride (9.32 g, 30.11 mmol)in anhydrous tetrahydrofuran (150 mL) was added to it by cannula. Thereaction mixture was allowed to warm to ambient temperature and stirredfor 16 h. The reaction mixture was quenched by addition of saturatedammonium chloride solution (80 mL), and the aqueous layer was extractedwith ethyl acetate (3×80 mL). The combined organic layers were washedwith brine (100 mL), dried over magnesium sulfate, and filtered.Concentration of the filtrate in vacuo and purification of the residueby column chromatography, eluting with a gradient of 0 to 10% of ethylacetate in heptane, provided the title compound as a colorless solid(8.35 g, 59% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.74 (d, J=4.7 Hz, 1H),7.31 (d, J=4.6 Hz, 1H), 6.97 (ddd, J=9.9, 7.9, 2.1 Hz, 1H), 1.39 (s,9H); MS (ES+) m/z 472.8 (M+1), 474.8 (M+1).

Step 6. Preparation of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate

To a mixture of tert-butyl((3-bromo-2,4,6-trifluorophenyl)sulfonyl)-(isothiazol-3-yl)carbamate(10.9 g, 23.03 mmol) and(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine(5.40 g, 23.03 mmol) in anhydrous dimethyl sulfoxide (95 mL) was addedN,N-diisopropylethylamine (12.00 mL, 69.09 mmol) dropwise and thereaction mixture was stirred at ambient temperature for 3 h. Thereaction mixture was diluted with saturated aqueous ammonium chloridesolution (80 mL), and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine (250 mL), dried overanhydrous magnesium sulfate, and filtered. Concentration of the filtratein vacuo provided a residue, which was dissolved in a minimum amount ofdichloromethane. To it was then added dropwise heptane until thesolution became cloudy and the resulting mixture was triturated using anultrasonication bath. The precipitate was filtered off, washed withheptane (25 mL), and dried to afford the title compound (10.4 g, 66%yield) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J=4.6Hz, 1H), 7.31-7.29 (m, 1H), 7.28-7.21 (m, 1H), 7.08-6.98 (m, 2H), 6.54(dd, J=13.4, 1.7 Hz, 1H), 6.35-6.28 (m, 1H), 4.68-4.59 (m, 2H), 3.59 (s,2H), 3.28-3.18 (m, 2H), 1.82 (br s, 4H), 1.44-1.17 (m, 13H); MS (ES+)m/z 687.2 (M+1), 689.2 (M+1).

Step 7. Preparation of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate

To a mixture of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate(19.22 g, 27.95 mmol) and triethylamine (39.0 mL, 279.5 mmol) inanhydrous 1,4-dioxane (280 mL) was added formic acid (5.27 mL, 139.8mmol) and the mixture was sparged with argon for 20 minutes. To themixture was added tetrakis(triphenylphosphine)palladium(0) (3.23 g, 2.80mmol) and the reaction mixture was heated to 105° C. for 18 h. Aftercooling to ambient temperature, the mixture was concentrated in vacuo.The residue was diluted with ethyl acetate (250 mL) and saturatedaqueous sodium bicarbonate solution (150 mL). The layers were separatedand the aqueous layer was extracted with ethyl acetate (2×100 mL). Thecombined organic layers were filtered through a pad of celite. Thefiltrate was washed with brine (150 mL) and dried over magnesiumsulfate. Filtration and concentration of the filtrate in vacuo provideda residue, which was triturated in ethanol (150 mL). The obtained solidwas filtered off and purified by column chromatography, eluting with agradient of 0 to 20% of methanol in dichloromethane, to afford the titlecompound as colorless solid (8.81 g, 52% yield): MS (ES+) m/z 609.2(M+1).

Step 8. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide

To tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate(8.81 g, 14.47 mmol) was added ethanol (360 mL) and water (180 mL) andthe reaction mixture was heated to reflux for 5 h. After cooling toambient temperature, the reaction mixture was concentrated in vacuo. Theresidue was dissolved in hot ethanol and the obtained solution wasconcentrated in vacuo. The residue was triturated with ethanol toprovide the title compound as colorless solid (7.098 g, 96% yield): ¹HNMR (300 MHz, DMSO-d₆) δ 11.61 (s, 1H), 8.90 (d, J=4.7 Hz, 1H),7.41-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.18-7.10 (m, 1H), 6.91 (d, J=4.8Hz, 1H), 6.40-6.31 (m, 2H), 4.47-4.31 (m, 2H), 3.53 (s, 2H), 3.11 (s,2H), 1.75-1.52 (m, 4H), 1.32-1.12 (m, 4H); ¹³C NMR (151 MHz, DMSO) δ160.9, 160.6, 157.2, 153.5, 150.6, 141.7, 129.3, 125.7, 123.3, 114.2,114.1, 102.7, 94.8, 58.8, 48.6, 36.9, 27.9; ¹⁹F NMR (565 MHz, DMSO) δ−108.5, −117.7; MS (ES+) m/z 509.0 (M+1).

Example 2 Synthesis of2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

Step 1. Preparation of Tert-Butyl Thiazol-4-ylcarbamate

To a solution of thiazole-4-carboxylic acid (150.0 g, 1.16 mol) inanhydrous tert-butanol (1000 mL) was slowly added triethylamine (156.7g, 1.55 mol) and diphenyl phosphoryl azide (383.6 g, 1.39 mol). Thereaction mixture was stirred at ambient temperature for 0.5 h and thenheated to 90° C. for 3 h. After cooling to ambient temperature, thereaction mixture was concentrated under reduced pressure. The obtainedresidue was diluted with petroleum ether (1000 mL) and water (1000 mL),and the mixture was stirred at ambient temperature for 12 h. The mixturewas filtered and the filter cake was extracted with ethyl acetate(3×1000 mL). The combined organic phase was washed with brine (3×1000mL), dried over anhydrous sodium sulfate, and filtered. Concentration ofthe filtrate provided a residue which was triturated with methanol (200mL) to give the title compound as a yellowish solid (100.0 g, 43%yield): ¹H NMR (400 MHz, CDCl₃) δ 89.92 (br s, 1H), 8.65 (d, J=2.4 Hz,1H), 7.35 (br s, 1H), 1.57 (s, 9H); MS (ES+) m/z 223.0 (M+23).

Step 2. Preparation of tert-butylthiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate

To a solution of tert-butyl thiazol-4-ylcarbamate (140.0 g, 699.1 mmol)in anhydrous tetrahydrofuran (700 mL) was added a 1 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (758.9 mL, 758.9mmol) at −78° C. The reaction mixture was allowed to warm to 0° C. andstirred for 20 minutes. After cooling the reaction mixture to −78° C., asolution of 2,4,6-trifluorobenzenesulfonyl chloride (175.0 g, 758.9mmol) in anhydrous tetrahydrofuran (200 mL) was slowly added to it. Thereaction mixture was allowed to warm to ambient temperature, stirred for12 h, and then quenched by addition of saturated aqueous ammoniumchloride (200 mL). The mixture was extracted with ethyl acetate (3×1000mL). The organic phase was washed with brine (3×1000 mL), dried overanhydrous sodium sulfate, and filtered. Concentration in vacuo andtrituration of the residue in methanol (100 mL) provided the titlecompound as a colorless solid (140.0 g, 58% yield): ¹H NMR (400 MHz,CDCl₃) δ 8.81 (d, J=2.1 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 6.85 (br t,J=8.4 Hz, 2H), 1.39 (s, 9H); MS (ES+) m/z 417.0 (M+23).

Step 3. Preparation of 2-bromo-3,6-difluorobenzaldehyde

To a solution of 2-bromo-1,4-difluorobenzene (100 g, 518 mmol) inanhydrous tetrahydrofuran (500 mL) was added a solution of lithiumdiisopropylamide (61.1 g, 570 mmol) in anhydrous tetrahydrofuran (100mL) over 30 minutes at −78° C. The reaction mixture was then stirred at−78° C. for 1 h, and N,N-dimethylformamide (45.5 g, 622 mmol) was addedto it. The reaction mixture was stirred at −78° C. for 30 minutes, andthen quenched by addition of saturated aqueous ammonium chloride (200mL). The mixture was allowed to warm to ambient temperature andextracted with ethyl acetate (500 mL). The combined extracts were driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo. Purification of the residue by columnchromatography, eluting with 5% of ethyl acetate in petroleum ether,provided the title compound as a colorless oil (69.0 g, 60% yield): ¹HNMR (400 MHz, CDCl₃) δ 10.35-10.20 (m, 1H), 7.27 (ddd, J=9.2, 7.4, 4.4Hz, 1H), 7.08 (dt, J=9.2, 4.0, Hz, 1H).

Step 4. Preparation of 2-bromo-3-fluoro-6-methoxybenzaldehyde

To anhydrous methanol (750 mL) was slowly added sodium metal (8.62 g,375 mmol) in several portions over the course of 1 h. After the lastaddition, the mixture was stirred for additional 10 minutes until allsodium was dissolved. To the mixture was then added2-bromo-3,6-difluorobenzaldehyde (75.0 g, 341 mmol) and the reactionmixture was heated to reflux for 20 h. After cooling to ambienttemperature, the reaction mixture was concentrated in vacuo. The residuewas dissolved in ethyl acetate (800 mL) and washed with saturatedaqueous ammonium chloride solution (2×400 mL). The aqueous layers wereextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (2×100 mL), dried over anhydrous magnesiumsulfate, and filtered. Concentration of the filtrate in vacuo yielded awaxy yellow solid that was used without further purification (82.6 g,quantitative yield): ¹H NMR (300 MHz, CDCl₃) δ 10.39 (d, J=0.8 Hz, 1H),7.32-7.28 (m, 1H), 6.95 (dd, J=9.2, 3.8 Hz, 1H), 3.94 (s, 3H).

Step 5. Preparation ofN-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine

To a flask charged with 2-bromo-3-fluoro-6-methoxybenzaldehyde (82.6 g,354.4 mmol) were added anhydrous dichloromethane (1500 mL), glacialacetic acid (1 mL), and N-methylpropan-2-amine (40 g, 459 mmol). Thereaction flask was placed in a water bath at 21° C., and sodiumcyanoborohydride (13.35 g, 212.6 mmol) was added to the reaction mixturein 5 portions (2.67 g), waiting 30 minutes between each addition. Afterstirring the reaction mixture at ambient temperature for 8 h, moreN-methylpropan-2-amine (7.0 g, 96.0 mmol) was added to it. The reactionmixture was stirred at ambient temperature for a further 16 h, and thenquenched by addition of 1 M sodium hydroxide solution (200 mL). Thelayers were separated, and the volume of the organic phase was reducedby half in vacuo. The remaining organic phase was washed with 1 M sodiumhydroxide solution (200 mL), brine (200 mL), and dried over anhydrousmagnesium sulfate. Filtration and concentration of the filtrate in vacuoprovided a residue, which was dissolved in ethyl acetate (400 mL) andextracted with 3 M hydrochloric acid (100 mL, 50 mL, and 30 mL). Thecombined aqueous layers were cooled to 0° C., the pH was adjusted to pH12 with solid sodium hydroxide, and the aqueous layer was extracted withethyl acetate (3×200 mL). The combined organic layers were washed with 1M sodium hydroxide solution (100 mL), brine (200 mL), and dried overanhydrous magnesium sulfate. Filtration and concentration of thefiltrate in vacuo provided the title compound as a red oil (81.4 g, 79%yield), which was used without further purification: ¹H NMR (300 MHz,CDCl₃) δ 7.02 (dd, J=9.0, 8.0 Hz, 1H), 6.79 (dd, J=9.0, 4.2 Hz, 1H),3.83 (s, 3H), 3.70 (s, 2H), 3.02 (dt, J=13.2, 6.6 Hz, 1H), 2.20 (s, 3H),1.13 (d, J=6.6 Hz, 6H).

Step 6. Preparation of(E)-6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzaldehydeOxime

To a flask charged withN-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine (10.0 g,34.5 mmol) was added anhydrous tetrahydrofuran (140 mL). The solutionwas cooled to an internal temperature of 0° C. using an ice-water bath.The bath was removed and a 1.3 M solution of isopropylmagnesium chloridelithium chloride complex in tetrahydrofuran (53 mL, 69 mmol) was addeddropwise via an addition funnel over the course of 45 minutes. Thereaction mixture was then stirred at ambient temperature for 10 minutes,and additional 1.3 M solution of isopropylmagnesium chloride lithiumchloride complex in tetrahydrofuran (53 mL, 69 mmol) was added dropwiseover the course of 45 minutes. The reaction mixture was stirred atambient temperature for 30 minutes and N,N-dimethylformamide (13 mL,172.3 mmol) was added to it. After stirring at ambient temperature for 3h, a solution of hydroxylamine hydrochloride (14.4 g, 206.8 mmol) inwater (40 mL) was added and the reaction mixture was stirred vigorouslyat ambient temperature for 16 h. To the reaction mixture was then addeda brine/water mixture (1:1, 200 mL) and the aqueous layer was extractedwith ethyl acetate (2×50 mL). The combined organic extracts were washedwith brine (2×50 mL), dried over anhydrous magnesium sulfate, andfiltered. Concentration of the filtrate in vacuo provided a residuewhich was purified by column chromatography, eluting with a gradient of20 to 80% of ethyl acetate (containing 10% of 2-propanol and 10% oftriethylamine) in heptane, to afford the title compound as a yellow wax(6.20 g, 71% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.51 (s, 1H), 7.00 (t,J=9.6 Hz, 1H), 6.83 (dd, J=9.1, 4.2 Hz, 1H), 3.82 (d, J=3.2 Hz, 3H),3.69 (s, 2H), 2.89 (t, J=6.6 Hz, 1H), 2.10 (s, 3H), 1.10-1.06 (m, 6H),OH not observed.

Step 7. Preparation ofN-(2-(aminomethyl)-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine

To a flask charged with(E)-6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzaldehydeoxime (36.8 g, 145 mmol) was added glacial acetic acid (690 mL). To itwas then added zinc powder (56 g, 868 mmol) and the reaction mixture washeated to 65° C. for 1 h. A second portion of zinc powder (56 g, 868mmol) was added to it and the reaction mixture was heated to 65° C. for1 h. After cooling to ambient temperature, the reaction mixture wasfiltered through a bed of celite, and the filter cake was washed withethyl acetate (2×100 mL). The combined filtrate was concentrated invacuo and the residue was dissolved in ethyl acetate (500 mL). To theorganic phase was added 5 M sodium hydroxide until the aqueous layer ofthe mixture had reached pH 12. The aqueous layer was extracted withethyl acetate (2×200 mL). The combined organic layers were washed withbrine (200 mL), dried over anhydrous magnesium sulfate, and filtered.Concentration of the filtrate in vacuo provided the title compound as ared oil (36.4 g, quantitative yield), which was used without furtherpurification: ¹H NMR (300 MHz, CDCl₃) δ 6.95 (t, J=9.1 Hz, 1H), 6.73(dd, J=9.0, 4.4 Hz, 1H), 3.84 (d, J=2.2 Hz, 2H), 3.79 (s, 3H), 3.67 (s,2H), 2.99-2.83 (m, 1H), 2.47-2.42 (m, 2H), 2.08 (s, 3H), 1.08 (d, J=6.6Hz, 6H).

Step 8. Preparation of tert-butyl((2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)-amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate

To a mixture of tert-butylthiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate (26.26 g, 66.58mmol) and N,N-diisopropylethylamine (23.2 mL, 133.2 mmol) in anhydrousdimethyl sulfoxide (190 mL) was added a solution ofN-(2-(aminomethyl)-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine(21.00 g, 87.38 mmol) in anhydrous dimethyl sulfoxide (60 mL) via adropping funnel over 40 minutes. The reaction mixture was stirred atambient temperature for 18 h. The mixture was then diluted with ethylacetate (400 mL) and washed with saturated aqueous sodium bicarbonate(250 mL). The aqueous layer was extracted with ethyl acetate (200 mL).The combined organic layers were washed with saturated aqueous sodiumbicarbonate (200 mL), saturated ammonium chloride (200 mL), brine (100mL), dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated in vacuo to a total volume of approximately 150 mL andcooled to 5° C. The obtained precipitate was filtered off and washedwith ethyl acetate (50 mL) to afford the title compound as a colorlesssolid (14.73 g, 36% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.79 (d, J=2.3 Hz,1H), 8.37 (s, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.02 (t, J=9.0 Hz, 1H), 6.83(dd, J=9.2, 4.4 Hz, 1H), 6.20 (d, J=12.1 Hz, 2H), 4.35 (s, 2H), 3.82 (s,3H), 3.70 (s, 2H), 2.99-2.85 (m, 1H), 2.13 (s, 3H), 1.40 (s, 9H), 1.13(d, J=6.6 Hz, 6H); MS (ES+) m/z 615.2 (M+1).

Step 9. Preparation of2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

To a flask containing tert-butyl((2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)-methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate(19.67 g, 32.01 mmol) was added 2-butanol (100 mL) and water (40 mL).The slurry was degassed by sparging with nitrogen for 15 minutes andthen heated to reflux for 24 h. The suspension was then cooled toapproximately 50° C., and diluted with ethanol (100 mL). The mixture washeated to reflux for an additional 1 h, and then cooled to 35° C. Theprecipitate was filtered off and rinsed with ethanol (60 mL) to affordthe title compound as an off-white solid (15.09 g, 92% yield): ¹H NMR(300 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.89 (d, J=2.2 Hz, 1H), 7.42 (s,1H), 7.14 (t, J=9.2 Hz, 1H), 7.02 (dd, J=9.2, 4.6 Hz, 1H), 6.88 (d,J=2.2 Hz, 1H), 6.37 (d, J=12.7 Hz, 2H), 4.36 (s, 2H), 3.77 (s, 3H), 3.58(s, 2H), 2.83-2.70 (m, 1H), 1.98 (s, 3H), 0.95 (d, J=6.6 Hz, 6H); MS(ES+) m/z 515.0 (M+1).

Example 3 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide

Step 1. Preparation of Tert-Butylthiazol-4-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate

To a solution of tert-butyl thiazol-4-ylcarbamate (2.87 g, 14.3 mmol) inanhydrous tetrahydrofuran 50 mL) was added a 1 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (14.3 mL, 14.3 mmol) at −50°C. The reaction mixture was allowed to warm to 0° C. and stirred for 1h. After cooling the reaction mixture to 0° C., a solution of2,3,4-trifluorobenzenesulfonyl chloride (3.0 g, 13.0 mmol) in anhydroustetrahydrofuran (60 mL) was slowly added to the reaction mixture. Thereaction mixture was allowed to warm to ambient temperature, stirred for12 h, and then quenched by addition of saturated aqueous ammoniumchloride (50 mL). The mixture was extracted with ethyl acetate (3×100mL). The combined organic phase was washed with brine (2×50 mL), driedover anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by columnchromatography, eluting with a gradient of 0-30% of ethyl acetate inheptane, to provide the title compound as a colorless solid (4.34 g, 85%yield): ¹H NMR (400 MHz, CDCl₃) δ 8.73 (d, J=2.2 Hz, 1H), 7.93-7.82 (m,1H), 7.47 (d, J=2.4 Hz, 1H), 7.11 (ddt, J=2.2, 6.8, 9.0 Hz, 1H), 1.29(s, 9H); MS (ES+) m/z 295.0 (M−99).

Step 2. Preparation of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

To a solution of(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine(1.19 g, 5.08 mmol) and tert-butylthiazol-4-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate (1.82 g, 4.62mmol) in anhydrous dimethyl sulfoxide (35 mL) was addedN,N-diisopropylethylamine (2.4 mL, 13.9 mmol)). The reaction mixture wasstirred at ambient temperature for 3 h. The reaction mixture was thenadded dropwise to a rapidly stirring aqueous ammonium chloride solution(500 mL) and the obtained precipitate was filtered off. The precipitatewas dissolved in ethyl acetate (250 mL) with washed with brine (2×50mL), dried over anhydrous sodium sulfate and filtered. Concentration ofthe filtrate in vacuo and purification of the residue by columnchromatography, eluting with a gradient of 0 to 35% of ethyl acetate(containing 10% of 2-propanol and 10% of trimethylamine) in heptane,provided the title compound as a colourless solid (1.09 g, 39% yield):MS (ES+) m/z 609.1 (M+1).

Step 3. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide

To a suspension of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate(1.09 g, 1.79 mmol) in water (20 mL) was added ethanol (40 mL) and thereaction mixture was heated to 80° C. for 8 h. The reaction mixture wasfiltered hot through a pad of celite and then concentrated in vacuo toprovide a wet slurry. To this was added ethanol (750 mL) and the mixturewas heated until a clear solution was obtained. Concentration in vacuoprovided a residue which was redissolved in ethanol (750 mL).Concentration in vacuo provided a residue was triturated with a minimalamount of ethanol to provide the title compound as a colourless solid(0.85 g, 93% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.13-11.12 (m, 1H),8.87 (d, J=2.2 Hz, 1H), 7.46-7.40 (m, 1H), 7.32 (td, J=7.8, 5.9 Hz, 1H),7.18-7.12 (m, 3H), 6.96 (d, J=2.2 Hz, 1H), 6.92-6.86 (m, 1H), 4.52-4.51(m, 2H), 3.59 (s, 2H), 3.15 (s, 2H), 1.72-1.69 (m, 4H), 1.26 (d, J=6.7Hz, 4H); ¹⁹F NMR (565 MHz, DMSO-d₆) δ −116.6, −137.9, −160.7; MS (ES+)m/z 509.0 (M+1), 510.0 (M+1).

Example 4 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide

Step 1. Preparation of3-bromo-2,4,6-trifluoro-N-(isoxazol-3-yl)benzenesulfonamide

To a mixture of isoxazol-3-amine (3.96 g, 47.2 mmol),4-(dimethylamino)-pyridine (1.10 g, 9.00 mmol) and pyridine (9.09 mL,112.5 mmol) in anhydrous dichloromethane (40 mL) was added a solution of3-bromo-2,4,6-trifluorobenzene-1-sulfonyl chloride (14.0 g, 45.0 mmol)in anhydrous dichloromethane (50 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 0.5 h and at ambient temperature for 12 h. Afterconcentration in vacuo, the residue was purified by columnchromatography, eluting with a gradient of 30 to 80% of ethyl acetate inheptane, to yield the title compound as a colourless solid (6.65 g, 40%yield): ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=1.8 Hz, 1H), 6.94 (ddd,J=10.0, 7.8, 2.2 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H), NH not observed; ¹⁹FNMR (376 MHz, CDCl₃) δ −90.8 (m, 1F), −96.0 (d, J=9.2 Hz, 1F), −104.3(d, J=12.6 Hz, 1F).

Step 2. Preparation of3-bromo-2,4,6-trifluoro-N-(isoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide

To a mixture of3-bromo-2,4,6-trifluoro-N-(isoxazol-3-yl)benzenesulfonamide (6.71 g,18.8 mmol) and potassium carbonate (5.18 g, 37.6 mmol) in anhydrousN,N-dimethylformamide (100 mL) was added 2-(trimethylsilyl)ethoxymethylchloride (3.76 g, 22.5 mmol) at 0° C. The reaction mixture was allowedto warm to ambient temperature and stirred for 2 h. The reaction mixturewas then quenched by addition of water (300 mL), and extracted withethyl acetate (3×150 mL). The combined organic layers were washed withbrine (3×100 mL), dried over anhydrous sodium sulfate, and filtered.Concentration of the filtrate under reduced pressure and purification ofthe residue by column chromatography, eluting with a gradient of 0 to20% of ethyl acetate in heptane, provided the title compound as a yellowsolid (8.24 g, 90% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=1.8 Hz,1H), 6.89 (ddd, J=10.1, 7.8, 2.2 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 5.42(s, 2H), 3.77-3.66 (m, 2H), 0.96-0.84 (m, 2H), 0.00 (s, 9H).

Step 3. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2,6-difluoro-N-(isoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide

To a mixture of3-bromo-2,4,6-trifluoro-N-(isoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (8.24 g, 16.9 mmol) and(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine(4.15 g, 17.8 mmol) in anhydrous dimethyl sulfoxide (150 mL) was addedN,N-diisopropylethylamine (6.56 g/8.8 mL, 50.7 mmol) and the reactionmixture was stirred at ambient temperature for 12 h. The reactionmixture was then added slowly to a rapidly stirring aqueous ammoniumchloride solution (1500 mL) and the obtained precipitate was filteredoff. The precipitate was then dissolved in ethyl acetate (500 mL). Theorganic phase was washed with brine (2×100 mL), dried over anhydroussodium sulfate, and filtered. Concentration of the filtrate in vacuo andpurification of the residue by column chromatography, eluting with agradient of 0 to 20% of ethyl acetate (containing 10% of 2-propanol and10% of trimethylamine) in heptane, provided the title compound as acolourless solid (6.23 g, 53% yield): MS (ES+) m/z 701.0 (M+1), 703.0(M+1).

Step 4. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide

To a suspension of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2,6-difluoro-N-(isoxazol-3-yl)-N-((2-(trimethylsilyl)ethoxy)-methyl)benzenesulfonamide(5.33 g, 7.60 mmol) and potassium phosphate tribasic (9.7 g, 45.6 mmol)in anhydrous 1,4-dioxane (190 mL) was added methylboronic acid (3.64 g,60.8 mmol) and the mixture was degassed by sparging with argon for 15minutes. To it was then added tetrakis(triphenylphosphine)palladium(0)(0.88 g, 0.76 mmol) and the reaction mixture was heated to 90° C. for 4h. After cooling to ambient temperature, the reaction mixture wasfiltered through a plug of celite. The filter cake was washed with1,4-dioxane (2×50 mL) and the combined filtrate was concentrated invacuo. Purification of the residue by column chromatography, elutingwith a gradient of 0 to 15% of ethyl acetate (containing 10% of2-propanol and 10% of trimethylamine) in heptane, provided the titlecompound as a colourless solid (4.01 g, 83% yield): ¹H NMR (300 MHz,DMSO-d₆) δ 8.82 (d, J=1.8 Hz, 1H), 7.35-7.28 (m, 1H), 7.23-7.20 (m, 1H),7.14-7.07 (m, 1H), 6.64-6.54 (m, 3H), 5.28 (s, 2H), 4.54 (dd, J=4.6, 0.3Hz, 2H), 3.57 (dd, J=17.7, 9.7 Hz, 4H), 3.11 (dd, J=0.9, 0.5 Hz, 2H),1.88 (d, J=2.0 Hz, 3H), 1.68-1.64 (m, 4H), 1.24-1.22 (m, 4H), 0.81 (t,J=8.0 Hz, 2H), −0.06 (s, 9H); MS (ES+) m/z 637.2 (M+1).

Step 5. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide

To a mixture of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide(6.33 g, 9.94 mmol) in 1,2-dichloroethane (300 mL) was addedtrifluoroacetic acid (35 mL, 400 mmol) and the reaction mixture wasstirred at ambient temperature for 4 h. Concentration in vacuo andpurification of the residue by column chromatography, eluting with agradient of 0-50% of ethyl acetate in heptane, followed by a gradient of0-15% of methanol in dichloromethane, provided the title compound as acolorless solid as its trifluoroacetic acid salt. The material wasdissolved in dichloromethane (500 mL) and washed with saturated aqueoussodium bicarbonate solution (2×200 mL). The combined aqueous layers wereextracted with dichloromethane (3×200 mL). The combined organic layerswere partially concentrated, then diluted with an equal volume ofacetone, and further concentrated. The procedure of partiallyconcentrating and diluting with acetone was repeated four times beforethe organic phase was concentrated to dryness. The residual solid wastriturated with acetone to provide the title compound as a colourlesssolid (3.10 g, 62% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.43-11.31 (m,1H), 8.62 (d, J=1.5 Hz, 1H), 7.34 (dt, J=7.8, 5.8 Hz, 1H), 7.26-7.23 (m,1H), 7.18-7.11 (m, 1H), 6.51 (d, J=14.0 Hz, 1H), 6.41-6.37 (m, 1H), 6.28(d, J=1.8 Hz, 1H), 4.50-4.49 (m, 2H), 3.64 (s, 2H), 3.29-3.26 (m, 2H),1.89 (d, J=1.9 Hz, 3H), 1.74-1.68 (m, 4H), 1.31-1.26 (m, 4H); ¹⁹F NMR(565 MHz, DMSO) δ −111.0, −112.2, −116.9; MS (ES+) m/z 507.1 (M+1).

Example 5 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of tert-butyl((3-bromo-2,4-difluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate

To a solution of tert-butyl isoxazol-3-ylcarbamate (3.81 g, 20.7 mmol)in anhydrous tetrahydrofuran (160 mL) was added a 1 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (26 mL, 26.0 mmol)at −78° C. The reaction mixture was stirred for 10 minutes at −78° C.,and then allowed to warm to ambient temperature and stirred for 1 h.After cooling the reaction mixture to −78° C., a cold (−78° C.) solutionof 3-bromo-2,4-difluorobenzenesulfonyl chloride (6.00 g, 20.7 mmol) inanhydrous tetrahydrofuran (100 mL) was added to it by cannula. Thereaction mixture was allowed to warm to ambient temperature and stirredfor 16 h. The reaction mixture was diluted with ethyl acetate (300 mL)and quenched by addition of saturated aqueous ammonium chloride solution(100 mL). The aqueous layer was separated and extracted with ethylacetate (2×100 mL). The combined organic layers were washed with brine(100 mL), dried over anhydrous magnesium sulfate, and filtered.Concentration of the filtrate in vacuo and purification of the residueby trituration in diethyl ether (20 mL), provided the title compound asa pale yellow solid (3.50 g, 39% yield): ¹H NMR (300 MHz, DMSO-d₆) δ9.14 (d, J=1.8 Hz, 1H), 8.16 (ddd, J=9.1, 8.1, 5.8 Hz, 1H), 7.63 (ddd,J=9.2, 7.8, 1.5 Hz, 1H), 6.97 (t, J=1.6 Hz, 1H), 1.30 (s, 9H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −93.4, −98.0; MS (ES+) m/z 438.9 (M+1), 441.0(M+1).

Step 2. Preparation of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2-fluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate

To a mixture of tert-butyl((3-bromo-2,4-difluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate (0.439 g,1.00 mmol) and(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine(0.258 g, 1.10 mmol) in anhydrous dimethyl sulfoxide (10 mL) was addedN,N-diisopropylethylamine (0.522 mL, 3.00 mmol) dropwise and thereaction mixture was stirred at ambient temperature for 14 h. Thereaction mixture was diluted with ethyl acetate (150 mL) and aqueousammonium chloride solution (50 mL) and the layers were separated. Theaqueous phase was extracted with ethyl acetate (3×50 mL). The combinedorganic phases were washed with brine (3×30 mL), dried over anhydroussodium sulfate, filtered and concentrated to yield the title compound asa yellow solid (0.269 g, 41% yield) which was used without furtherpurification: MS (ES+) m/z 653.2 (M+1), 655.2 (M+1)).

Step 3. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide2,2,2-trifluoroacetate

To a suspension of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-bromo-2-fluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate(0.269 g, 0.412 mmol) and potassium phosphate tribasic (0.350 g, 1.65mmol) in anhydrous 1,4-dioxane (10 mL) was added methylboronic acid(0.148 g, 2.47 mmol) and the mixture was degassed by sparging with argonfor 15 minutes. To it was then addedtetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.041 mmol) and thereaction mixture was heated to 90° C. for 4 h. After cooling to ambienttemperature, the reaction mixture was filtered through a plug of celite.The filter cake was washed with 1,4-dioxane (2×50 mL) and the combinedfiltrate was concentrated in vacuo. The resulting residue was dissolvedin dichloromethane (10 mL) and trifluoroacetic acid (5 mL) under anatmosphere of nitrogen. The reaction mixture was stirred at ambienttemperature for 2 h. The reaction mixture was concentrated in vacuo andthe residue was purified by preparative reverse phase HPLC usingacetonitrile in water containing 0.1% trifluoroacetic acid as eluent, toyield the title compound as a colorless solid (0.057 g, 22% yield): ¹HNMR (300 MHz, DMSO-d₆) δ 11.52 (s, 1H), 9.55-9.52 (m, 1H), 8.67 (d,J=1.8 Hz, 1H), 7.60-7.32 (m, 4H), 6.60 (d, J=9.0 Hz, 1H), 6.36-6.32 (m,2H), 4.48 (td, J=1.2, 0.5 Hz, 2H), 4.35-4.33 (m, 2H), 4.14 (s, 2H),2.20-2.16 (m, 2H), 1.97-1.90 (m, 5H), 1.76-1.67 (m, 4H); MS (ES+) m/z489.1 (M+1).

Example 6 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of tert-butyl((3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

To a solution of tert-butyl N-thiazol-4-ylcarbamate (110 g, 549 mmol) intetrahydrofuran (1000 mL) was added lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 659 mL, 659 mmol) at −78° C. The mixture waswarmed to 5° C. before a cooled (−78° C.) solution of3-chloro-2,4-difluorobenzenesulfonyl chloride (163 g, 659 mmol) intetrahydrofuran (300 mL) was added to it dropwise. The reaction mixturewas stirred at ambient temperature for 12 h. The reaction mixture wasdiluted with saturated aqueous ammonium chloride (200 mL) and extractedwith ethyl acetate (3×1000 mL). The combined organic layers were washedwith brine (3×1000 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The residue was triturated with methanol (300mL) to give the title compound as a colorless solid (75 g, 33% yield):¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.26-8.09 (m, 1H), 8.03 (s, 1H),7.66 (t, J=8.6 Hz, 1H), 1.27 (s, 9H); MS (ES+) m/z 432.8 (M+23), 434.8(M+23).

Step 2. Preparation of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

To a suspension of tert-butyl((3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.410 g,1.00 mmol) and(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine(0.258 g, 1.10 mmol) in anhydrous dimethyl sulfoxide (10 mL) was addedN,N-diisopropylethylamine (0.522 mL, 3.00 mmol) and the reaction mixturewas stirred at ambient temperature for 14 h. The reaction mixture wasdiluted with ethyl acetate (150 mL) and aqueous ammonium chloridesolution (50 mL) and the layers were separated. The aqueous phase wasextracted with ethyl acetate (3×50 mL). The combined organic phases werewashed with brine (3×30 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to yield the title compound as ayellow solid (0.338 g, 54% yield) which was used without furtherpurification: MS (ES+) m/z 625.2 (M+1), 627.2 (M+1)).

Step 3. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

To a solution of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate(0.200 g, 0.320 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (10 mL) and the the reaction mixture was stirred atambient temperature for 2 h. The reaction mixture was then concentratedin vacuo and the residue was purified by preparative reverse phase HPLCusing acetonitrile in water containing 0.1% trifluoroacetic acid aseluent, to yield the title compound as a colorless solid (0.102 g, 50%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.21 (s, 1H), 9.61-9.57 (m, 1H),8.88 (d, J=2.2 Hz, 1H), 7.60 (t, J=8.5 Hz, 1H), 7.53-7.31 (m, 3H), 6.98(d, J=2.2 Hz, 1H), 6.90-6.87 (m, 1H), 6.72 (d, J=9.1 Hz, 1H), 4.56-4.55(m, 2H), 4.37-4.36 (m, 2H), 4.16 (d, J=0.3 Hz, 2H), 2.21-2.18 (m, 2H),1.94-1.91 (m, 2H), 1.77-1.66 (m, 4H); MS (ES+) m/z 525.1 (M+1), 527.1(M+1).

Example 7 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

To a microwave vial was added tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate(0.138 g, 0.221 mmol), potassium phosphate tribasic (0.141 g, 0.663mmol), methylboronic acid (0.106 g, 1.77 mmol), tricyclohexylphosphinetetrafluoroborate (0.275 g, 0.75 mmol) and anhydrous 1,4-dioxane (4 mL).The resulting suspension was degassed by sparging with argon for 15minutes before palladium(II) acetate (0.007 g, 0.033 mmol) was added toit. The vial was sealed and then heated in a microwave reactor to 120°C. for 3 h. After cooling to ambient temperature, the reaction mixturewas filtered through a plug of celite. The filter cake was washed with1,4-dioxane (2×50 mL) and the combined filtrate was concentrated invacuo. The resulting residue was dissolved in dichloromethane (5 mL) andtrifluoroacetic acid (5 mL) was added to it. The reaction mixture wasstirred at ambient temperature for 2 h. The reaction mixture wasconcentrated in vacuo and the residue was purified by preparativereverse phase HPLC using acetonitrile in water containing 0.1%trifluoroacetic acid as eluent, to yield the title compound as acolorless solid (0.043 g, 31% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.05(s, 1H), 9.50 (ddd, J=2.6, 1.4, 0.7 Hz, 1H), 8.86 (d, J=2.2 Hz, 1H),7.55-7.32 (m, 4H), 6.88 (d, J=2.2 Hz, 1H), 6.56 (d, J=8.9 Hz, 1H),6.27-6.24 (m, 1H), 4.46 (dd, J=2.5, 0.7 Hz, 2H), 4.33 (d, J=4.9 Hz, 2H),4.13 (d, J=0.4 Hz, 2H), 2.19-2.15 (m, 2H), 1.96 (d, J=1.8 Hz, 3H),1.96-1.89 (m, 2H), 1.75-1.66 (m, 4H); MS (ES+) m/z 505.1 (M+1).

Example 8 Synthesis of2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

Step 1. Preparation of 2-bromo-3-fluoro-6-hydroxybenzaldehyde

To a solution of 2-bromo-3-fluoro-6-methoxybenzaldehyde (5.0 g, 21.5mmol) in anhydrous dichloromethane (100 mL) was slowly added borontribromide (2.5 mL, 25.8 mmol) at −78° C. The reaction was then allowedto warm to ambient temperature and stirred for 18 h. The solution wascooled to 0° C. and quenched by addition of saturated aqueous ammoniumchloride (100 mL). The aqueous layer was extracted with dichloromethane(2×100 mL) and the combined organic layers were washed with brine (2×50mL), dried over anhydrous magnesium sulfate, and filtered. Concentrationof the filtrate in vacuo and purification of the residue by columnchromatography, eluting with 0 to 100% of ethyl acetate in heptane,provided the title compound as a colorless oil (2.35 g, 50% yield): ¹HNMR (300 MHz, DMSO-d₆) δ 11.37-11.31 (m, 1H), 10.23 (d, J=16.2 Hz, 1H),7.58 (dd, J=9.1, 8.5 Hz, 1H), 7.05 (dd, J=9.2, 4.3 Hz, 1H).

Step 2. Preparation of 2-bromo-3-fluoro-6-isopropoxybenzaldehyde

To a mixture of 2-bromo-3-fluoro-6-hydroxybenzaldehyde (1.41 g, 6.44mmol) and potassium carbonate (2.67 g, 19.3 mmol) in anhydrousN,N-dimethylformamide (35 mL) was added 2-iodopropane (0.77 mL, 7.73mmol) and the reaction was heated to 60° C. for 18 h. The reaction wasthen allowed to cool to ambient temperature, and diluted with ethylacetate (50 mL) and water (50 mL). The aqueous layer was extracted withethyl acetate (3×50 mL) and the combined organic layers were washed withbrine (2×50 mL), dried over anhydrous magnesium sulfate, and filtered.Concentration of the filtrate in vacuo and purification of the residueby column chromatography, eluting with a gradient of 5 to 60% of ethylacetate in heptane, afforded the title compound as a yellow oil (1.68 g,quantitative yield): ¹H NMR (300 MHz, CDCl₃) δ 10.39 (d, J=1.2 Hz, 1H),7.29-7.24 (m, 1H), 6.96 (dd, J=9.2, 3.9 Hz, 1H), 4.61 (sept, J=6.1 Hz,1H), 1.39 (d, J=6.0 Hz, 6H).

Step 3. Preparation ofN-(2-bromo-3-fluoro-6-isopropoxybenzyl)-N-methylpropan-2-amine

To a mixture of 2-bromo-3-fluoro-6-isopropoxybenzaldehyde (1.67 g, 6.44mmol) and N-methylpropan-2-amine (1.3 mL, 12.88 mmol) in anhydrousdichloromethane (32 mL) was added sodium triacetoxyborohydride (6.25 g,29.6 mmol). The reaction mixture was stirred at ambient temperature for18 h and then quenched by addition of saturated aqueous ammoniumchloride solution (50 mL). The aqueous layer was extracted withdichloromethane (3×50 mL) and the combined organic layers were washedwith brine (50 mL), dried over anhydrous magnesium sulfate, andfiltered. Concentration of the filtrate in vacuo and purification of theresidue by column chromatography, eluting with a gradient of 0-20% ofmethanol in dichloromethane, afforded the title compound as a colorlessoil (2.05 g, quantitative yield): MS (ES+) m/z 318.0 (M+1), 320.0 (M+1).

Step 4. Preparation of(E)-6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzaldehydeOxime

To a flask charged withN-(2-bromo-3-fluoro-6-isopropoxybenzyl)-N-methylpropan-2-amine (2.05 g,6.44 mmol) was added anhydrous tetrahydrofuran (13 mL) and the mixturewas cooled to an internal temperature of 0° C. using an ice-water bath.To it was then added a 1.3 M solution of isopropylmagnesium chloridelithium chloride complex in tetrahydrofuran (9.7 mL, 19.32 mmol). Thereaction mixture was stirred at 0° C. for 30 minutes and a secondportion of 1.3 M solution of isopropylmagnesium chloride lithiumchloride complex in tetrahydrofuran (9.7 mL, 19.32 mmol) was added toit. The reaction mixture was stirred at 0° C. for 30 minutes, afterwhich anhydrous N,N-dimethylformamide (5 mL, 64.4 mmol) was added to it.The reaction mixture was allowed to warm to ambient temperature andstirred for 45 minutes. To it was then added a 50% solution ofhydroxylamine hydrochloride in water (4.3 mL, 64.4 mmol) and thereaction mixture was stirred vigorously at ambient temperature for 18 h.The reaction mixture was diluted with ethyl acetate (100 mL) and water(100 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL),and the combined organic layers were washed with brine (100 mL), driedover anhydrous magnesium sulfate, and filtered. Concentration of thefiltrate in vacuo and purification of the residue by columnchromatography, eluting with a gradient of 10 to 70% of ethyl acetate(containing 10% of 2-propanol and 10% of triethylamine) in heptane,afforded the title compound as a colorless solid (0.778 g, 43% yield):MS (ES+) m/z 283.2 (M+1).

Step 5. Preparation ofN-(2-(aminomethyl)-3-fluoro-6-isopropoxybenzyl)-N-methylpropan-2-amine

To(E)-6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzaldehydeoxime (0.778 g, 2.75 mmol) was added glacial acetic acid (14 mL) and themixture was stirred for 15 minutes before being cooled in a water/icebath. To it was then added zinc powder (1.07 g, 16.5 mmol) and thereaction mixture was heated to 60° C. for 1.5 h. After cooling toambient temperature, the reaction mixture was filtered, and the filtercake was washed with dichloromethane (3×50 mL). The combined organicfiltrate was washed with saturated aqueous sodium bicarbonate solution(3×100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, andfiltered. Concentration of the filtrate in vacuo afforded the titlecompound as an orange wax (0.498 g, 67% yield) that was used withoutfurther purification: ¹H NMR (300 MHz, CDCl₃) δ 7.05-6.97 (m, 1H),6.84-6.79 (m, 1H), 4.56-4.49 (m, 1H), 4.14-4.09 (m, 2H), 3.91-3.84 (m,2H), 3.53-3.48 (m, 2H), 3.14-3.05 (m, 1H), 2.28-2.24 (m, 3H), 1.38-1.30(m, 6H), 1.17-1.08 (m, 6H).

Step 6. Preparation of2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

To a mixture of tert-butylthiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate (0.729 g, 1.85mmol) andN-(2-(aminomethyl)-3-fluoro-6-isopropoxybenzyl)-N-methylpropan-2-amine(0.498 g, 1.85 mmol) in anhydrous dimethyl sulfoxide (9 mL) was addedN,N-diisopropylethylamine (1.0 mL, 5.55 mmol). The reaction mixture wasstirred at ambient temperature for 18 h. The mixture was then dilutedwith ethyl acetate (50 mL) and saturated aqueous ammonium chloridesolution (50 mL). The aqueous layer was extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine (100 mL),dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated in vacuo and purified by column chromatography, elutingwith a gradient of 5 to 60% of ethyl acetate (containing 10% of2-propanol and 10% of triethylamine) in heptane to afford a colorlessoil. The oil was then dissolved in dichloromethane (10 mL) andtrifluoroacetic acid (2 mL) was added to it. The reaction mixture wasstirred at ambient temperature for 18 h and then concentrated in vacuo.Purification of the residue by column chromatography, eluting with agradient of 10 to 80% of ethyl acetate (containing 20% of ethanol and 2%of saturated ammonium hydroxide) in heptane, afforded the title compoundas a colorless solid (0.304 g, 31% yield): ¹H NMR (300 MHz, DMSO-d₆) δ11.22-11.08 (m, 1H), 8.89 (d, J=2.2 Hz, 1H), 7.45-7.42 (m, 1H),7.17-7.09 (m, 1H), 7.07-7.00 (m, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.38-6.33(m, 2H), 4.64-4.55 (m, 1H), 4.35-4.33 (m, 2H), 3.66-3.58 (m, 2H),2.88-2.62 (m, 1H), 2.09-2.01 (m, 3H), 1.26 (d, J=6.0 Hz, 6H), 1.01-0.97(m, 6H); MS (ES+) m/z 543.1 (M+1).

Example 9 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

To a mixture of2,4,6-trifluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide(0.44 g, 1.07 mmol, prepared according to PCT Published PatentApplication No. WO 2018/106284) and(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine(0.25 g, 1.07 mmol) in anhydrous dimethyl sulfoxide (10 mL) was addedpotassium carbonate (0.30 g, 2.14 mmol) and the reaction mixture wasstirred at ambient temperature for 16 h. The reaction mixture wasdiluted with saturated aqueous ammonium chloride solution (20 mL), andextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with water (40 mL), brine (40 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Purification of theresidue by column chromatography, eluting with a gradient of 0 to 40% ofethyl acetate (containing 10% of isopropanol and 10% of triethylamine)in hexanes, provided the title compound as a colorless solid (0.38 g,56% yield): MS (ES+) m/z 629.3 (M+1).

Step 2. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

To a solution of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide(0.38 g, 0.75 mmol) in anhydrous dichloromethane (3 mL) was addedtrifluoroacetic acid (3 mL) and the reaction mixture was heated toreflux for 16 h. After cooling to ambient temperature, the reactionmixture was concentrated in vacuo. Purification of the residue by columnchromatography, eluting with a gradient of 0 to 10% of methanol indichloromethane, afforded the title compound as colorless solid (0.29 g,62% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.23 (s, 1H), 9.56 (s, 1H),8.90 (d, J=2.2 Hz, 1H), 7.59-7.30 (m, 4H), 6.92 (d, J=2.1 Hz, 1H),6.41-6.32 (m, 2H), 4.39-4.06 (m, 6H), 2.22-2.06 (m, 2H), 2.01-1.86 (m,2H), 1.78-1.57 (m, 4H); MS (ES+) m/z 509.1 (M+1).

Example 10 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide

Step 1. Preparation of 2-bromo-3-(bromomethyl)-1,4-difluorobenzene

To a solution of (2-bromo-3,6-difluorophenyl)methanol (10.75 g. 48.20mmol, prepared according to PCT Published Patent Application No. WO2018/106284) in anhydrous dichloromethane (150 mL) at 0° C. was addedcarbon tetrabromide (25.58 g, 77.12 mmol) and triphenylphosphine (15.17g, 57.84 mmol). The reaction mixture was stirred at 0° C. for 2 h andthen concentrated in vacuo. Purification of the residue by columnchromatography, eluting with a gradient of 0 to 10% of ethyl acetate inheptane, afforded the title compound as colorless oil (8.51 g, 62%yield): ¹H NMR (300 MHz, CDCl₃): δ 7.14-7.01 (m, 2H), 4.66-4.61 (m, 2H);MS (ES+) m/z 286.0 (M+1), 288.0 (M+1).

Step 2. Preparation of7-(2-bromo-3,6-difluorobenzyl)-7-azabicyclo[2.2.1]heptane

Following the procedure as described in EXAMPLE 1, Step 1 and makingnon-critical variations as required to replace2-(bromomethyl)-6-fluorobenzonitrile with2-bromo-3-(bromomethyl)-1,4-difluorobenzene, the title compound wasobtained as a colorless solid (5.15 g, 98% yield): MS (ES+) m/z 302.0(M+1), 304.0 (M+1).

Step 3. Preparation of(E)-2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzaldehydeOxime

Following the procedure as described in EXAMPLE 2, Step 6, and makingnon-critical variations as required to replaceN-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine with7-(2-bromo-3,6-difluorobenzyl)-7-azabicyclo[2.2.1]heptane, the titlecompound was obtained as a colorless solid (1.02 g, 97% yield): MS (ES+)m/z 267.2 (M+1).

Step 4. Preparation of(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorophenyl)methanamine

To a solution of(E)-2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzaldehydeoxime (0.53 g, 1.98 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C.was added a 1 M solution of lithium aluminum hydride in tetrahydrofuran(4.0 mL, 4.0 mmol). The reaction mixture was stirred at 0° C. for 15minutes, and at ambient temperature for 16 h, and then heated underreflux for 30 minutes. The reaction mixture was cooled to 0° C. andsodium sulfate decahydrate (4.0 g) was added to it in small portions.The reaction mixture was stirred at 0° C. for 30 minutes and then atambient temperature for 1.5 h. The mixture was filtered, and the filtercake was rinsed with ethyl acetate (2×10 mL). The combined filtrate wasdried over anhydrous magnesium sulfate. Filtration and concentration ofthe filtrate in vacuo afforded the title compound as a brown oil (0.45g, 90% yield): MS (ES+) m/z 253.2 (M+1).

Step 5. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

Following the procedure as described in EXAMPLE 9, Step 1 and makingnon-critical variations as required to replace(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanaminewith of(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorophenyl)methanamine,the title compound was obtained as a colorless solid (0.19 g, 16%yield): MS (ES+) m/z 647.2 (M+1).

Step 6. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide

Following the procedure as described in EXAMPLE 9, Step 2 and makingnon-critical variations as required to replace4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamidewith4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide,the title compound was obtained as a colorless solid (0.096 g, 52%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.18 (br s, 1H), 8.89 (d, J=2.2 Hz,1H), 7.46-7.21 (m, 3H), 6.90 (d, J=2.2 Hz, 1H), 6.42-6.30 (m, 2H),4.51-4.39 (m, 2H), 3.61 (br s, 2H), 3.13 (br s, 2H), 1.68 (br s, 4H),1.29 (br s, 4H); MS (ES+) m/z 527.1 (M+1).

Example 11 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of (2-bromo-3-fluoro-6-methoxyphenyl)methanol

To a solution of 2-bromo-3-fluoro-6-methoxybenzaldehyde (4.19 g, 17.98mmol) in anhydrous methanol (37 mL) was added sodium borohydride (1.36g, 35.96 mmol) at 0° C. in small portions. The reaction mixture wasstirred at 0° C. for 1h and then concentrated in vacuo. The residue wasdiluted with saturated aqueous ammonium chloride solution (100 mL), andextracted with ethyl acetate (3×60 mL). The combined organic layers werewashed with water (50 mL), brine (60 mL), dried over anhydrous magnesiumsulfate, and filtered. Concentration of the filtrate in vacuo affordedthe title compound as a colorless solid (4.23 g, quantitative yield): MS(ES+) m/z 258.0 (M+1), 259.8 (M+1).

Step 2. Preparation of 2-bromo-3-(bromomethyl)-1-fluoro-4-methoxybenzene

Following the procedure as described in EXAMPLE 10, Step 1 and makingnon-critical variations as required to replace(2-bromo-3,6-difluorophenyl)methanol with(2-bromo-3-fluoro-6-methoxyphenyl)methanol, the title compound wasobtained as a colorless solid (2.85 g, 53% yield): ¹H NMR (300 MHz,CDCl₃) δ 7.12-7.03 (m, 1H), 6.84-6.78 (m, 1H), 4.75-4.70 (m, 2H), 3.90(s, 3H).

Step 3. Preparation of7-(2-bromo-3-fluoro-6-methoxybenzyl)-7-azabicyclo[2.2.1]-heptane

Following the procedure as described in EXAMPLE 1, Step 1 and makingnon-critical variations as required to replace2-(bromomethyl)-6-fluorobenzonitrile with2-bromo-3-(bromomethyl)-1-fluoro-4-methoxybenzene, the title compoundwas obtained as a colorless solid (2.09 g, 70% yield): MS (ES+) m/z314.0 (M+1), 316.0 (M+1).

Step 4. Preparation of(E)-2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzaldehydeOxime

Following the procedure as described in EXAMPLE 2, Step 6 and makingnon-critical variations as required to replaceN-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine with7-(2-bromo-3-fluoro-6-methoxybenzyl)-7-azabicyclo[2.2.1]heptane, thetitle compound was obtained as a colorless solid (1.9 g, 51% yield): MS(ES+) m/z 279.2 (M+1).

Step 5. Preparation of(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxyphenyl)methanamine

Following the procedure as described in EXAMPLE 2, Step 7 and makingnon-critical variations as required to replace(E)-6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzaldehydeoxime with(E)-2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzaldehydeoxime, the title compound was obtained as a colorless solid (0.84 g, 46%yield): MS (ES+) m/z 265.2 (M+1).

Step 6. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

Following the procedure as described in EXAMPLE 9, Step 1 and makingnon-critical variations as required to replace(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanaminewith of(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxyphenyl)methanamine,the title compound was obtained as a colorless solid (0.13 g, 21%yield): MS (ES+) m/z 659.2 (M+1).

Step 7. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Following the procedure as described in EXAMPLE 9, Step 2 and makingnon-critical variations as required to replace4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamidewith4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide,the title compound was obtained as a colorless solid (0.096 g, 75%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.23 (s, 1H), 9.18 (s, 1H), 8.90(d, J=2.2 Hz, 1H), 7.40-7.31 (m, 1H), 7.20-7.12 (m, 1H), 6.91 (d, J=2.1Hz, 1H), 6.58 (s, 1H), 6.40-6.31 (m, 2H), 4.39-4.29 (m, 2H), 4.24-4.01(m, 4H), 3.86 (s, 3H), 2.26-2.09 (m, 2H), 1.97-1.81 (m, 2H), 1.77-1.51(m, 4H); MS (ES+) m/z 539.1 (M+1).

Example 12 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

To a mixture of tert-butylthiazol-4-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate (0.39 g, 0.99mmol) and(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxyphenyl)methanamine(0.26 g, 0.99 mmol) in anhydrous dimethyl sulfoxide (10 mL) was addedpotassium carbonate (0.27 g, 1.98 mmol) and the reaction mixture wasstirred at ambient temperature for 16 h. The reaction mixture wasdiluted with saturated aqueous ammonium chloride solution (30 mL), andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (50 mL), brine (50 mL), dried over anhydrous magnesiumsulfate, and filtered. Concentration of the filtrate in vacuo andpurification of the residue by column chromatography, eluting with agradient of 0 to 40% of ethyl acetate (containing 10% of isopropanol and10% of triethylamine) in hexanes, provided the title compound as acolorless solid (0.12 g, 19% yield): MS (ES+) m/z 639.2 (M+1).

Step 2. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

To a solution of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate(0.12 g, 0.19 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (0.72 mL, 9.39 mmol). The reaction mixture was stirred at ambienttemperature for 3 h, and then concentrated in vacuo. Purification of theresidue by column chromatography, eluting with a gradient of 0 to 10% ofmethanol in dichloromethane, afforded the title compound as colorlesssolid (0.101 g, 81% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.21 (s, 1H),9.07-8.84 (m, 2H), 7.49-7.41 (m, 1H), 7.37-7.29 (m, 1H), 7.19-7.10 (m,1H), 7.09-7.01 (m, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.81-6.72 (m, 1H),4.51-4.41 (m, 2H), 4.30-3.95 (m, 4H), 3.85 (s, 3H), 2.28-2.06 (m, 2H),1.93-1.55 (m, 6H); MS (ES+) m/z 539.0 (M+1).

Example 13 Synthesis of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of Tert-Butylisothiazol-3-yl((2,3,4-trifluorophenyl)sulfonyl)-carbamate

Following the procedure as described in EXAMPLE 1, Step 5 and makingnon-critical variations as required to replace3-bromo-2,4,6-trifluorobenzenesulfonyl chloride with2,3,4-trifluorobenzenesulfonyl chloride, the title compound was obtainedas a colorless solid (2.74 g, 46% yield): MS (ES+) m/z 395.0 (M+1).

Step 2. Preparation of tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate

To a mixture of tert-butylisothiazol-3-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate (0.51 g, 1.30mmol) and(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorophenyl)methanamine(0.31 g, 1.30 mmol) in anhydrous dimethyl sulfoxide (13 mL) was addedpotassium carbonate (0.36 g, 2.60 mmol) and the reaction mixture wasstirred at ambient temperature for 16 h. The reaction mixture wasdiluted with saturated aqueous ammonium chloride solution (30 mL), andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (50 mL), brine (50 mL), dried over anhydrous magnesiumsulfate, and filtered. Concentration of the filtrate in vacuo andpurification of the residue by column chromatography, eluting with agradient of 0 to 40% of ethyl acetate (containing 10% of isopropanol and10% of triethylamine) in hexanes, provided the title compound as acolorless solid (0.144 g, 18% yield): MS (ES+) m/z 609.4 (M+1)

Step 3. Preparation of4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide2,2,2-trifluoroacetate

Following the procedure as described in EXAMPLE 12, Step 2 and makingnon-critical variations as required to replace tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamatewith tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate,the title compound was obtained as a colorless solid (0.146 g, 96%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.69 (s, 1H), 9.30 (s, 1H), 8.91(d, J=4.7 Hz, 1H), 7.59-7.51 (m, 1H), 7.49-7.43 (m, 1H), 7.40-7.27 (m,2H), 7.15-7.07 (m, 1H), 6.94-6.92 (m, 1H), 6.86-6.76 (m, 1H), 4.49 (dd,J=3.8, 0.4 Hz, 2H), 4.30-4.12 (m, 2H), 4.08-3.87 (m, 2H), 2.22-1.82 (m,4H), 1.75-1.49 (m, 4H); MS (ES+) m/z 509.0 (M+1).

Example 14 Synthesis of4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of 1-(2-bromo-3,6-difluorophenyl)ethan-1-ol

To a solution of 2-bromo-3,6-difluorobenzaldehyde (1 g, 4.53 mmol) inanhydrous diethyl ether was slowly added a 3 M solution ofmethylmagnesium bromide in diethyl ether (2 mL, 5 89 mmol) at −10° C.The reaction mixture was stirred at −10° C. for 3 h after which anadditional amount of a 3 M solution of methylmagnesium bromide indiethyl ether (4.53 mL, 13.59 mmol) was added dropwise to it. Thereaction mixture was stirred at −10° C. for 1 h, and then poured into astirred saturated aqueous ammonium chloride solution at 0° C. in smallportions. The mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous magnesium sulfate, and filtered. Concentration of the filtratein vacuo and purification of the residue by column chromatography,eluting with a gradient of 0 to 20% of ethyl acetate in hexanes,provided the title compound as a colorless oil (0.97 g, 91% yield): ¹HNMR (300 MHz, CDCl₃) δ 7.07-6.99 (m, 2H), 5.41-5.30 (m, 1H), 2.56-2.44(m, 1H), 1.65-1.59 (m, 3H); MS (ES+) m/z 260.2 (M+23), 262.1 (M+23).

Step 2. Preparation of 2-bromo-3-(1-bromoethyl)-1,4-difluorobenzene

Following the procedure as described in EXAMPLE 10, Step 1 and makingnon-critical variations as required to replace(2-bromo-3,6-difluorophenyl)methanol with1-(2-bromo-3,6-difluorophenyl)ethan-1-ol, the title compound wasobtained as a colorless solid (8.24 g, 65% yield): ¹H NMR (300 MHz,CDCl₃) δ 7.12-6.99 (m, 2H), 5.72-5.57 (m, 1H), 2.18-2.04 (m, 3H).

Step 3. Preparation of7-(1-(2-bromo-3,6-difluorophenyl)ethyl)-7-azabicyclo[2.2.1]heptane

To a mixture of 2-bromo-3-(1-bromoethyl)-1,4-difluorobenzene (4.2 g,14.0 mmol) and 7-azabicyclo[2.2.1]heptane hydrochloride (1.87 g, 14.0mmol) in anhydrous dimethyl sulfoxide (25 mL) was added potassiumcarbonate (3.87 g, 28.0 mmol). The reaction mixture was stirred atambient temperature for 16 h, and then at 80° C. for 4 h. The reactionmixture was allowed to cool to ambient temperature, diluted with water(100 mL), and extracted with ethyl acetate (3×60 mL). The combinedorganic layers were washed with brine (80 mL), dried over anhydroussodium sulfate, and filtered. Concentration of the filtrate in vacuo andpurification of the residue by column chromatography, eluting with agradient of 0 to 10% methanol in dichloromethane, afforded the titlecompound as a pale yellow oil (2.83 g, 64% yield): MS (ES+) m/z 316.1(M+1), 318.1 (M+1).

Step 4. Preparation of(E)-2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzaldehydeOxime

Following the procedure as described in EXAMPLE 2, Step 6 and makingnon-critical variations as required to replaceN-(2-bromo-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine with7-(1-(2-bromo-3,6-difluorophenyl)ethyl)-7-azabicyclo[2.2.1]heptane, thetitle compound was obtained as a colorless solid (0.635 g, 27% yield):MS (ES+) m/z 281.2 (M+1).

Step 5. Preparation of(2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorophenyl)methanamine

Following the procedure as described in EXAMPLE 2, Step 7 and makingnon-critical variations as required to replace(E)-6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzaldehydeoxime with(E)-2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzaldehydeoxime, the title compound was obtained as a pale yellow oil (0.53 g, 88%yield): MS (ES+) m/z 267.2 (M+1).

Step 6. Preparation of tert-butyl((4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

To a mixture tert-butylthiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate (0.77 g, 1.95mmol) and(2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorophenyl)methanamine(0.52 g, 1.95 mmol) in anhydrous dimethyl sulfoxide (20 mL) was addedN,N-diisopropylethylamine (1.02 mL, 5.85 mmol) and the reaction mixturewas stirred at ambient temperature for 16 h. The reaction mixture wasdiluted with saturated aqueous ammonium chloride solution (30 mL), andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (50 mL), brine (50 mL), dried over anhydrous magnesiumsulfate, and filtered. Concentration of the filtrate in vacuo andpurification of the residue by column chromatography, eluting with agradient of 0 to 40% of ethyl acetate (containing 10% of isopropanol and10% of triethylamine) in hexanes, provided the title compound as acolorless solid (0.58 g, 46% yield): MS (ES+) m/z 641.3 (M+1).

Step 7. Preparation of4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Following the procedure as described in EXAMPLE 12, Step 2 and makingnon-critical variations as required to replace tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamatewith tert-butyl((4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate,the title compound was obtained as a colorless solid (0.47 g, 83%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.24 (s, 1H), 9.49-9.34 (m, 1H),8.90 (d, J=2.2 Hz, 1H), 7.57-7.44 (m, 2H), 7.45-7.36 (m, 1H), 6.92 (d,J=2.2 Hz, 1H), 6.45-6.31 (m, 2H), 4.47-4.11 (m, 4H), 3.60 (s, 1H),2.28-2.08 (m, 2H), 1.98-1.47 (m, 9H); MS (ES+) m/z 541.3 (M+1).

Example 15A and 15B Synthesis of(S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamideand(R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide

To a mixture of4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate (0.100 g, 0.153 mmol) in ethyl acetate (50 mL)and water (10 mL) was added aqueous ammonium hydroxide (0.2 mL of a25-28% solution). The reaction mixture was stirred at 25° C. for 30minutes. The organic layer was separated, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. Purification and resolution of the residue by preparativesupercritical fluid chromatography, using 30% of ethanol (containing0.1% of ammonium hydroxide) in supercritical carbon dioxide as eluentand a Chiralpak AS column (250×30 mm, 5 μm), provided(S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide(colorless solid, 0.014 g, 17% yield, 99% ee) as the first elutingenantiomer and(R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide(colorless solid, 0.015 g, 18% yield, 96% ee) as the second elutingenantiomer. The absolute configuration was arbitrarily assigned. Datafor(S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide:¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=2.4 Hz, 1H), 7.04 (d, J=2.4 Hz,1H), 6.97-7.00 (m, 2H), 6.10-6.13 (m, 2H), 4.72 (d, J=13.6 Hz, 1H), 4.43(dd, J=13.6, 2.8 Hz, 1H), 4.13-4.19 (m, 1H), 3.62 (brs, 1H), 2.93 (m,1H), 1.90-1.96 (m, 2H), 1.72-1.78 (m, 2H), 1.41-1.43 (m, 4H), 1.28-1.37(m, 3H), 2 NH not observed; ¹⁹F NMR (376 MHz, CDCl₃) δ −107.8 (s, 2F),−119.0 (d, J=17.6, 1F), −119.6 (d, J=17.5, 1F); MS (ES+) m/z 541.4(M+1). Data for(R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide:¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.4 Hz,1H), 6.90-7.00 (m, 2H), 6.10-6.13 (m, 2H), 4.72 (d, J=13.6 Hz, 1H), 4.42(dd, J=13.6, 2.8 Hz, 1H), 4.13-4.18 (m, 1H), 3.62 (brs, 1H), 2.93 (m,1H), 1.90-1.96 (m, 2H), 1.72-1.78 (m, 2H), 1.41-1.43 (m, 4H), 1.28-1.37(m, 3H), 2 NH not observed; ¹⁹F NMR (376 MHz, CDCl₃) δ −107.7 (s, 2F),−119.0 (d, J=17.5, 1F), −119.6 (d, J=17.4, 1F); MS (ES+) m/z 541.4(M+1).

Example 16 Synthesis of2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

Step 1. Preparation of tert-butyl((2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate

Following the procedure as described in EXAMPLE 12, Step 1 and makingnon-critical variations as required to replace(2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxyphenyl)methanaminewith ofN-(2-(aminomethyl)-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine, thetitle compound was obtained as a colorless solid (0.06 g, 12% yield): MS(ES+) m/z 615.2 (M+1).

Step 2. Preparation of2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

Following the procedure as described in EXAMPLE 12, Step 2 and makingnon-critical variations as required to replace tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamatewith tert-butyl((2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate,the title compound was obtained as a colorless solid (0.059, 97%): ¹HNMR (300 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.88 (d, J=2.2 Hz, 1H), 7.69 (s,1H), 7.47-7.38 (m, 1H), 7.26-7.13 (m, 1H), 7.09-7.01 (m, 1H), 6.99-6.95(m, 1H), 6.89-6.76 (m, 1H), 4.52-4.37 (m, 2H), 3.95-3.61 (m, 5H), 2.91(br s, 1H), 2.09 (br s, 3H), 1.08 (br s, 6H); MS (ES+) m/z 515.1 (M+1).

Example 17 Synthesis of5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of tert-butyl((5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate

To a mixture of tert-butyl((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.85 g,2.08 mmol, prepared according to U.S. Published Patent Application No.2017/0334902) andN-(2-(aminomethyl)-3-fluoro-6-methoxybenzyl)-N-methylpropan-2-amine(0.50 g, 2.08 mmol) in anhydrous dimethyl sulfoxide (17 mL) was addedN,N-diisopropylethylamine (1.09 mL, 6.24 mmol) and the reaction mixturewas stirred at ambient temperature for 16 h. The reaction mixture wasdiluted with saturated aqueous ammonium chloride solution (30 mL), andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (50 mL), brine (50 mL), dried over anhydrous magnesiumsulfate, and filtered. Concentration in vacuo and purification of theresidue by column chromatography, eluting with a gradient of 0 to 40% ofethyl acetate (containing 10% of isopropanol and 10% of triethylamine)in hexanes, provided the title compound as a colorless solid (0.60 g,46% yield): MS (ES+) m/z 631.1 (M+1), 633.1 (M+1).

Step 2. Preparation of5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Following the procedure as described in EXAMPLE 12, Step 2 and makingnon-critical variations as required to replace tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamatewith tert-butyl((5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamatethe title compound was obtained as a colorless solid (0.139, 90%): ¹HNMR (300 MHz, DMSO-d₆) δ 11.17 (s, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.42 (s,1H), 7.61 (d, J=7.4 Hz, 1H), 7.42-7.36 (m, 1H), 7.21-7.09 (m, 1H), 7.00(t, J=1.9 Hz, 1H), 6.86-6.78 (m, 1H), 6.75-6.71 (m, 1H), 4.59-4.36 (m,3H), 4.21-4.06 (m, 1H), 3.83 (s, 3H), 3.68-3.54 (m, 1H), 2.59 (d, J=4.3Hz, 3H), 1.33 (dd, J=15.4, 6.4 Hz, 6H); MS (ES+) m/z 531.0 (M+1), 533.0(M+1).

Example 18 Synthesis of2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Step 1. Preparation of tert-butyl((2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methylphenyl)sulfonyl)(thiazol-4-yl)carbamate

To a mixture of tert-butyl((5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)phenyl)sulfonyl)(thiazol-4-yl)carbamate(0.26 g, 0.41 mmol) and methylboronic acid (0.196 g, 3.28 mmol) inanhydrous 1,4-dioxane (10 mL) was added potassium phosphate tribasic(0.21 g, 1.24 mmol) and the mixture was purged with argon for 20minutes. To it was then tricyclohexylphosphonium tetrafluoroborate (0.45g, 0.12 mmol) and palladium(II) acetate (0.014 g, 0.062 mmol) and theresulting mixture was heated at 105° C. After cooling to ambienttemperature, the reaction mixture was filtered through a pad of celite.The filter pad was washed with ethyl acetate (20 mL) and the combinedfiltrate was concentrated in vacuo. The obtained residue was dilutedwith saturated aqueous ammonium chloride solution (20 mL), and extractedwith ethyl acetate (3×30 mL). The combined organic layers were washedwith brine (40 mL), dried over anhydrous magnesium sulfate, andfiltered. Concentration of the filtrate in vacuo and purification of theresidue by column chromatography, eluting with a gradient of 0 to 10% ofmethanol in dichloromethane, provided the title compound as a pale brownoil (0.25 g, quantitative yield): MS (ES+) m/z 611.1 (M+1).

Step 2. Preparation of2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate

Following the procedure as described in EXAMPLE 12, Step 2 and makingnon-critical variations as required to replace tert-butyl((4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamatewith tert-butyl((2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methylphenyl)sulfonyl)(thiazol-4-yl)carbamate,the title compound was obtained as a colorless solid (0.131, 51%): ¹HNMR (300 MHz, DMSO-d₆) δ 11.00 (s, 1H), 8.86 (d, J=2.2 Hz, 1H), 8.42 (s,1H), 7.44-7.35 (m, 2H), 7.19-7.12 (m, 1H), 6.88 (d, J=2.2 Hz, 1H), 6.49(d, J=13.7 Hz, 1H), 6.28-6.21 (m, 1H), 4.50-4.30 (m, 3H), 4.18-4.05 (m,1H), 3.84 (s, 3H), 3.66-3.52 (m, 1H), 2.60 (d, J=4.8 Hz, 3H), 2.03 (s,3H), 1.31 (dd, J=15.0, 6.5 Hz, 6H); MS (ES+) m/z 511.1 (M+1).

Biological Assays

Various techniques are known in the art for testing the activity of thecompound of the invention or determining their solubility in knownpharmaceutically acceptable excipients. In order that the inventiondescribed herein may be more fully understood, the following biologicalassays are set forth. It should be understood that these examples arefor illustrative purposes only and are not to be construed as limitingthis invention in any manner.

Biological Example 1 Electrophysiological Assay (In Vitro Assay)

Patch voltage clamp electrophysiology allows for the direct measurementand quantification of block of voltage-gated sodium channels (Na_(V)'s),and allows the determination of the time- and voltage-dependence ofblock which has been interpreted as differential binding to the resting,open, and inactivated states of the sodium channel (Hille, B., Journalof General Physiology (1977), 69: 497-515).

The following patch voltage clamp electrophysiology studies may beperformed on representative compounds of the invention using humanembryonic kidney cells (HEK), permanently transfected with an expressionvector containing the full-length cDNA coding for the desired humansodium channel α-subunit, grown in culture media containing 10% FBS, 1%PSG, and 0.5 mg/mL G418 at 37° C. with 5% CO₂. HEK cells used for theelectrophysiology (EP) recordings have a passage number of less than 40for all studies and are used within three days from the time of plating.Na_(V)1.1, Na_(V)1.5 and Na_(V)1.6 cDNAs (NM_001165964 (SCN1A),NM_000335 (SCN5A) and NM_014191 (SCN8A), respectively) are stablyexpressed in HEK-293 cells.

Sodium currents are measured using the patch clamp technique in thewhole-cell configuration using either a PatchXpress automated voltageclamp or manually using an Axopatch 200B (Axon Instruments) or Model2400 (A-M systems) amplifier. The manual voltage clamp protocol is asfollows: Borosilicate glass micropipettes are fire-polished to a tipdiameter yielding a resistance of 2-4 Mohms in the working solutions.The pipette is filled with a solution comprised of: 5 mM NaCl, 10 mMCsCl, 120 mM CsF, 0.1 mM CaCl₂, 2 mM MgCl₂, 10 mM HEPES, 10 mM EGTA; andadjusted to pH 7.2 with CsOH. The external solution has the followingcomposition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES;and adjusted to pH 7.4 with NaOH. In some studies, the external sodiumcan be reduced by equimolar replacement with choline. Osmolarity in theCsF internal and NaCl external solutions is adjusted to 300 mOsm/kg and310 mOsm/kg with glucose, respectively. All recordings are performed atambient temperature in a bath chamber with a volume of 150 μL. Controlsodium currents are measured in 0.5% DMSO. Controls and representativecompounds of the invention are applied to the recording chamber througha 4-pinch or 8-pinch valve bath perfusion system manufactured by ALAScientific Instruments.

Currents are recorded at 40 kHz sampling frequency, filtered at 5 Hz,and stored using a Digidata-1322A analogue/digital interface with thepClamp software (Axon Instruments). Series resistance compensation isapplied (60-80%). Cells are rejected if currents showed inadequatevoltage control (as judged by the IV relationship during stepwiseactivation). All statistics in this study are to be given as mean±SD.

The membrane potential is maintained at a voltage where inactivation ofthe channel is complete. The voltage is then stepped back to a verynegative (Vhold=−150 mV) voltage for 20 ms and then a test pulse isapplied to quantify the compound block. The 20 ms brief repolarizationis long enough for compound-free channels to completely recover fromfast inactivation, but the compound-bound channels recover more slowlysuch that negligible recovery could occur during this interval. Thepercent decrease in sodium current following wash-on of compound istaken as the percent block of sodium channels.

Biological Example 2 Sodium Influx Assay (In Vitro Assay)

This sodium influx assay employs the use of the cell permeable, sodiumsensitive dye ANG2 to quantify sodium ion influx through sodium channelswhich are maintained in an open state by use of sodium channelmodulators. This high throughput sodium influx assay allows for rapidprofiling and characterization of sodium channel blockers.

In general, Trex HEK293 cells were stably transfected with an inducibleexpression vector containing the full-length cDNA coding for the desiredhuman sodium channel α-subunit and with an expression vector containingfull length cDNA coding for the β1-subunit. Sodium channel expressingcell lines were induced with tetracycline (1 μg/mL) and plated on384-well PDL-coated plates at a density of 25K-30K cells/well in culturemedia (DMEM, containing 10% FBS and 1% L-glutamine). After overnightincubation (37° C., 5% CO₂), culture media was removed and cells wereloaded with 5 uM ANG2 dye for 1-1.5h in Buffer 1 (155 mM NMDG, 5 mM KCl,2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mM glucose, adjusted with Tristo pH 7.4). Access dye was removed and cells were incubated with testcompounds for 1 hr in buffer 1 containing sodium channel modulator(s) atroom temperature. Hamamatsu FDSS μCell was used to perform a 1:1addition of Na/K challenge buffer (140 mM NaCl, 20 mM HEPES, 1 mM CaCl₂,15 mM KCl, 1 mM MgCl₂, 10 mM glucose, adjusted with Tris to pH 7.4) andsimultaneously read plates at excitation wavelength of 530 nm andemission wavelength set at 558 nm. Percent inhibition of sodium ioninflux was calculated for each test compound at each test concentrationto determine the IC₅₀ values.

Representative compounds of the invention, when tested in this model,demonstrated affinities for the inactivated state of Na_(V)1.6,Na_(V)1.5 and Na_(V)1.1 as set forth below in Table 1.

The Example numbers provided in Table 1 correspond to the Examplenumbers herein and “Flux” refers to the Sodium Influx Assay:

TABLE 1 Inhibition of Nav1.1, Nav1.5, and Na_(V)1.6 Flux Na_(V)1.6 FluxNa_(V)1.5 Flux Na_(V)1.1 Ex. No. IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM)  10.015 >30.000 9.603  2 0.027 28.259 27.539  3 0.142 >30.000 >30.000  40.047 >30.000 16.982  5 0.617 >30.000 >30.000  6 0.095 15.272 5.227  70.181 21.314 7.441  8 0.026 11.074 27.982  9 0.026 20.428 7.845 10 0.02825.357 7.932 11 0.002 27.488 5.911 12 0.054 >30.000 >30.000 130.270 >30.000 23.741 14 0.653 12.787 >30.000 15a 0.530 >30.000 >30.00015b 0.821 >30.000 >30.000 16 0.031 9.459 >30.000 17 0.012 16.285 >30.00018 0.016 11.817 >30.000

Biological Example 3 Electrical Stimulation Seizure Assays

Many electric stimulation seizure tests have been used to identifycompounds with anti-convulsion activity, i.e., which raise seizurethreshold. Two examples of electrical stimulation seizure assaysfrequently used in the field are the 6 Hz psychomotor seizure assay (6Hz) and the Maximal Electroshock Seizure (MES). The 6 Hz assay isconsidered a model of partial seizures observed in humans (Löscher, W.and Schmidt, D., Epilepsy Res. (1988), Vol. 2, pp 145-81; Barton, M. E.et al., Epilepsy Res. (2001), Vol. 47, pp. 217-27). The MES assay is amodel for generalized tonic-clonic seizures in humans and provides anindication of a compound's ability to prevent seizure spread when allneuronal circuits in the brain are maximally active. These seizures arehighly reproducible and are electrophysiologically consistent with humanseizures (Toman et al., 1946; Piredda et al., 1984; White et al., 1995).Experiments can be performed with healthy animals, or with seizure proneanimals that have been genetically modified to model genetic epilepsysyndromes (Piredda, S. G. et al., J. Pharmacol. Exp. Ther. (1985), Vol.232, pp. 741-5; Toman, J. E. et al., J. Neurophysiol. (1946), Vol. 9,pp. 231-9; and White, H. S. et al., Ital. J. Neurol. Sci. (1995), Vol.16 (1-2), pp. 73-7).

To facilitate testing mice can be pretreated with the test compound orwith the appropriate vehicle prior to the application of theelectroshock. Each treatment group (n=4-8 mice/group) is examined foranticonvulsive effects at different time points after administration ofthe compound and the vehicle. The eyes of mice are first anesthetizedwith a topical application of Alcaine (proparacaine hydrochloride) 0.5%,one drop in each eye 30 minutes prior to the stimulation. Seizures arethen induced by placing electrodes on the eyes which deliver atranscorneal current.

The 6 Hz Psychomotor Seizure Test:

Following pretreatment, each mouse is challenged with the low-frequency(6 Hz, 0.3 ms pulse width) stimulation for 3 sec. delivered throughcorneal electrodes at several intensities (12-44 mA). Animals aremanually restrained and released immediately following the stimulationand observed for the presence or absence of seizure activity. Typically,the 6 Hz stimulation results in a seizure characterized by a minimalclonic phase that is followed by stereotyped, automatist behaviors,including twitching of the vibrissae, and Straub-tail or by ageneralized tonic clonic seizure. The presence, type and latency toseizure (in seconds) after the application of the current are monitored.Animals not displaying a clonic or generalized tonic clonic seizure areconsidered “protected”. All animals are euthanized at the end of assay.Plasma and brain samples are collected.

Maximal Electroshock Test (MES):

Following pretreatment, each mouse is challenged with an alternatingcurrent (60 Hz, 0.4-0.6 ms pulse width) for 0.2-0.5 sec. deliveredthrough corneal electrodes at intensities (44-55 mA).

Typically, the MES stimulation results in a generalized tonic seizurethat can be followed by a clonic seizure, automatist behaviors andStraub-tail. The presence, type and latency to seizure (in seconds)after the application of the current are monitored. An animal isconsidered “protected” from MES-induced seizures upon abolition of thehindlimb tonic extensor component of the seizure. After the seizure,mice are expected to resume normal exploratory behaviour within 1 to 4minutes. Latency to seizure is recorded with a cut-off of 1 minute afterwhich all animals are euthanized.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

1. A compound of formula (I):

wherein: q is 1 or 2; r is 1 or 2; R¹ is hydrogen or alkyl; R² isthiazolyl, isothiazolyl or isoxazolyl; R^(3a) and R^(3b) are eachindependently hydrogen or alkyl; each R⁴ is independently halo or alkyl;R⁵ is halo; each R⁶ is independently halo or alkoxy; R⁷ isazabicyclo[2.2.1]heptanylalkyl or R⁷ is ((methyl)(prop-2-yl)amino)alkylwhen r is 2 and at least one R⁶ is alkoxy; as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate or prodrug thereof.
 2. Thecompound of claim 1 wherein R⁷ is azabicyclo[2.2.1]heptanylalkyl.
 3. Thecompound of claim 2 wherein R² is isothiazolyl.
 4. The compound of claim3 selected from:4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)benzenesulfonamide;and4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(isothiazol-3-yl)benzenesulfonamide2,2,2-trifluoroacetate.
 5. The compound of claim 2 wherein R² isthiazolyl.
 6. The compound of claim 5 wherein r is
 1. 7. The compound ofclaim 6 selected from:4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide;4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate;4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate; and4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate.
 8. The compound of claim 5 where r is
 2. 9. Thecompound of claim 8 selected from:4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate;4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluoro-3-methoxybenzyl)amino)-2,3-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate;54-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate;(S)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;and(R)-4-((2-(1-(7-azabicyclo[2.2.1]heptan-7-yl)ethyl)-3,6-difluorobenzyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide.10. The compound of claim 2 wherein R² is isoxazolyl.
 11. The compoundof claim 10 selected from:4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2,6-difluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide;and4-((2-((7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-fluorobenzyl)amino)-2-fluoro-N-(isoxazol-3-yl)-3-methylbenzenesulfonamide2,2,2-trifluoroacetate.
 12. The compound of claim 1 where R⁷ is((methyl)(prop-2-yl)amino)alkyl, provided that r is 2 and at least oneR⁶ is alkoxy.
 13. The compound of claim 12 wherein R² is isothiazolyl.14. The compound of claim 12 wherein R² is thiazolyl.
 15. The compoundof claim 14 selected from:2,6-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;2,6-difluoro-4-((6-fluoro-3-isopropoxy-2-((isopropyl(methyl)amino)methyl)benzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;2,3-difluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate; and2-fluoro-4-((6-fluoro-2-((isopropyl(methyl)amino)methyl)-3-methoxybenzyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide2,2,2-trifluoroacetate.
 16. The compound of claim 12 wherein R² isisoxazolyl.
 17. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of claim 1, as astereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate or prodrug thereof.
 18. Amethod of treating a disease or a condition associated with Na_(V)1.6activity in a mammal wherein the disease or condition is epilepsy and/orepileptic seizure disorder and wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of claim 1, as a stereoisomer, enantiomer ortautomer thereof or a mixture thereof; or a pharmaceutically acceptablesalt, solvate or prodrug thereof.
 19. A method of decreasing ion fluxthrough Na_(V)1.6 in a mammalian cell, wherein the method comprisescontacting the cell with a compound of claim 1, as a stereoisomer,enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate or prodrug thereof.
 20. Amethod of selectively inhibiting a first voltage-gated sodium channelover a second voltage-gated sodium channel in a mammal, wherein themethod comprises administering to the mammal a modulating amount of acompound of claim 1, as a stereoisomer, enantiomer or tautomer thereofor a mixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof. 21.-23. (canceled)
 24. A method of preparing a compoundof formula (I):

wherein: q is 1 or 2; r is 1 or 2; R¹ is hydrogen or alkyl; R² isthiazolyl, isothiazolyl or isoxazolyl; R^(3a) and R^(3b) are eachindependently hydrogen or alkyl; each R⁴ is independently halo or alkyl;R⁵ is halo; each R⁶ is independently halo or alkoxy; R⁷ isazabicyclo[2.2.1]heptanylalkyl or R⁷ is ((methyl)(prop-2-yl)amino)alkylwhen r is 2 and at least one R⁶ is alkoxy; as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate or prodrug thereof; (a)wherein the compound of formula (I) is a compound of formula (Ia):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as defined above for thecompound of formula (I), n is 1 to 6 and R^(4b) is fluoro; and whereinthe method comprises treating a compound of formula (M):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R^(4b), R⁵ and R⁶ are as defined abovefor the compound of formula (Ia), n is 1 to 6 and R⁸ is alkyl; undersuitable conditions to yield a compound of formula (Ia), as definedabove; or the method comprises treating a compound of formula (Wa):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R^(4b), R⁵ and R⁶ are as defined abovefor the compound of formula (Ia), n is 1 to 6 and Pg¹ is anitrogen-protecting group; under suitable conditions to yield a compoundof formula (Ia), as defined above; or (b) wherein the compound offormula (I) is a compound of formula (Ib):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein R² and R⁵ are as described above for a compoundof formula (I), R⁴ is halo, R^(6a) is halo and R⁸ is alkyl; and whereinthe method comprises treating a compound of formula (T):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein R² and R⁵ are as described above for a compoundof formula (I), R⁴ is halo, R^(6a) is halo and each R⁸ is alkyl; undersuitable conditions to yield a compound of formula (Ib), as definedabove; or (c) wherein the compound of formula (I) is a compound offormula (Ic):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), n is 1 to 6 and R^(4c) is chloro or fluoro; orthe compound of formula (I) is a compound of formula (If):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), n is 1 to 6 and R^(4d) is alkyl; wherein themethod comprises treating a compound of formula (La):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), n is 1 to 6, R^(4c) is chloro or fluoro, and R⁸is alkyl; under suitable conditions to yield a compound of formula (Ic)or a compound of formula (If), as defined above; or (d) wherein thecompound of formula (I) is a compound of formula (Id):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), n is 1 to 6, R^(4b) is fluoro and R^(4d) isalkyl; and wherein the method comprises treating a compound of formula(X):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), R^(4b) is fluoro, R^(4d) is alkyl, n is 1 to 6and Pg¹ is nitrogen-protecting group; under suitable conditions to yielda compound of formula (Id) as defined above; or (e) wherein the compoundof formula (I) is a compound of formula (Ie):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), n is 1 to 6, and R^(4d) is alkyl; and whereinthe method comprises treating a compound of formula (Lc):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), n is 1 to 6, R^(4d) is alkyl and R⁸ is alkyl;under suitable conditions to yield a compound of formula (Ie) as definedabove; or (f) wherein the compound of formula (I) is a compound offormula (Ih):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), m is 0 to 5, R^(4b) is fluoro and R⁹ ishydrogen or methyl; and wherein the method comprises treating a compoundof formula (Wb):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein r, R², R⁵ and R⁶ are as described above for acompound of formula (I), m is 0 to 5, R^(4b) is fluoro, R⁹ is hydrogenor methyl and Pg¹ is a nitrogen-protecting group; under suitableconditions to yield a compound of formula (Ih) as defined above; or (g)wherein the compound of formula (I) is a compound of formula (Ii):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein R² and R⁵ are as described above for a compoundof formula (I), R^(4c) is chloro or bromo, R^(6a) is halo and R⁸ isalkyl; and wherein the method comprises treating a compound of formula(CC):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein R² and R⁵ are as described above for a compoundof formula (I), R^(4c) is chloro or bromo, R^(6a) is halo and each R⁸ isalkyl; under suitable conditions to yield a compound of formula (Ii) asdefined above; or (h) wherein the compound of formula (I) is a compoundof formula (Ij):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein R² and R⁵ are as described above for a compoundof formula (I), R^(4c) is chloro or bromo, R^(6a) is halo and R⁸ isalkyl; and wherein the method comprises treating a compound of formula(DD):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein R² and R⁵ are as described above for a compoundof formula (I), R^(4c) is chloro or bromo, R^(6a) is halo and each R⁸ isalkyl; under suitable conditions to yield a compound of formula (Ij) asdefined above; or (i) wherein the compound of formula (I) is a compoundof formula (Ik):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein R² and R⁵ are as described above for a compoundof formula (I), R^(4d) is alkyl, R^(6a) is halo and R⁸ is alkyl; andwherein the method comprises treating a compound of formula (EE):

as an individual stereoisomer, enantiomer or tautomer thereof or amixture thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof; wherein R² and R⁵ are as described above for a compoundof formula (I), R^(4d) is alkyl, R^(6a) is halo and each R⁸ is alkyl;under suitable conditions to yield a compound of formula (Ik) as definedabove.